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38830992 | 900 | Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial final results. | Claudin18.2 (CLDN18.2) is highly expressed with the development of various malignant tumors, especially gastrointestinal cancers, and is emerging as a new target for cancer treatment. Satricabtagene autoleucel (satri-cel)/CT041 is an autologous chimeric antigen receptor (CAR) T cell targeting CLDN18.2, and the interim results of the CT041-CG4006 trial were reported in June 2022. Here we present the final results of this single-arm, open-label, phase 1 trial, which evaluated the safety and efficacy of satri-cel in patients with CLDN18.2-positive advanced gastrointestinal cancers. This trial included a dose-escalation stage (n = 15) and a dose-expansion stage in four different cohorts (total n = 83): cohort 1, satri-cel monotherapy in 61 patients with standard chemotherapy-refractory gastrointestinal cancers; cohort 2, satri-cel plus anti-PD-1 therapy in 15 patients with standard chemotherapy-refractory gastrointestinal cancers; cohort 3, satri-cel as sequential treatment after first-line therapy in five patients with gastrointestinal cancers; and cohort 4, satri-cel monotherapy in two patients with anti-CLDN18.2 monoclonal antibody-refractory gastric cancer. The primary endpoint was safety; secondary endpoints included efficacy, pharmacokinetics and immunogenicity. A total of 98 patients received satri-cel infusion, among whom 89 were dosed with 2.5 × 10 | [
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] | 2024-06-04 | 42 | 38830992 | [
"gastrointestinal cancers",
"cancer treatment",
"patients",
"standard chemotherapy-refractory gastrointestinal cancers",
"anti-CLDN18.2 monoclonal antibody-refractory gastric cancer",
"CLDN18.2-positive advanced gastrointestinal cancers",
"cohort",
"various malignant tumors",
"secondary endpoints",
"sequential treatment",
"efficacy",
"especially gastrointestinal cancers",
"satri-cel infusion",
"safety",
"satri-cel",
", satri-cel monotherapy",
"cohort 2, satri-cel plus anti-PD-1 therapy",
"an autologous chimeric antigen receptor",
"CLDN18.2",
"CAR",
"cel)/CT041",
"CAR) T cell",
"four different cohorts",
"first",
"first-line therapy",
"the interim results",
"pharmacokinetics",
"15 patients",
"61 patients",
"five patients"
] | [] | 0 | 10.1038/s41591-024-03037-z
10.1200/JCO.23.02314 | [
"Qi",
"Liu",
"Gong",
"Liu",
"Wang",
"Zhang",
"Qin",
"Ge",
"Zhang",
"Peng",
"Zhou",
"Lu",
"Lu",
"Cao",
"Yuan",
"Wang",
"Wang",
"Xue",
"Peng",
"Wang",
"Yuan",
"Li",
"Zhang",
"Shen"
] | [
"State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Early Drug Development Centre, Peking University Cancer Hospital & Institute, Beijing, China. [email protected].",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Early Drug Development Centre, Peking University Cancer Hospital & Institute, Beijing, China.",
"State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China.",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Early Drug Development Centre, Peking University Cancer Hospital & Institute, Beijing, China.",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China.",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Early Drug Development Centre, Peking University Cancer Hospital & Institute, Beijing, China.",
"Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China.",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Early Drug Development Centre, Peking University Cancer Hospital & Institute, Beijing, China.",
"State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China.",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China.",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China.",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China.",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China.",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China.",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China.",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China.",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China.",
"CARsgen Therapeutics Co., Ltd., Shanghai, China.",
"CARsgen Therapeutics Co., Ltd., Shanghai, China.",
"CARsgen Therapeutics Co., Ltd., Shanghai, China.",
"State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China. [email protected].",
"State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China. [email protected].",
"State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China. [email protected]."
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] | [] | 8.559227 | 6.277403 |
38830795 | 901 | Comparison of seven CD19 CAR designs in engineering NK cells for enhancing anti-tumour activity. | Chimeric antigen receptor-natural killer (CAR-NK) cell therapy is emerging as a promising cancer treatment, with notable safety and source diversity benefits over CAR-T cells. This study focused on optimizing CAR constructs for NK cells to maximize their therapeutic potential. We designed seven CD19 CAR constructs and expressed them in NK cells using a retroviral system, assessing their tumour-killing efficacy and persistence. Results showed all constructs enhanced tumour-killing and prolonged survival in tumour-bearing mice. In particular, CAR1 (CD8 TMD-CD3ζ SD)-NK cells showed superior efficacy in treating tumour-bearing animals and exhibited enhanced persistence when combined with OX40 co-stimulatory domain. Of note, CAR1-NK cells were most effective at lower effector-to-target ratios, while CAR4 (CD8 TMD-OX40 CD- FcεRIγ SD) compromised NK cell expansion ability. Superior survival rates were noted in mice treated with CAR1-, CAR2 (CD8 TMD- FcεRIγ SD)-, CAR3 (CD8 TMD-OX40 CD- CD3ζ SD)- and CAR4-NK cells over those treated with CAR5 (CD28 TMD- FcεRIγ SD)-, CAR6 (CD8 TMD-4-1BB CD-CD3ζ 1-ITAM SD)- and CAR7 (CD8 TMD-OX40 CD-CD3ζ 1-ITAM SD)-NK cells, with CAR5-NK cells showing the weakest anti-tumour activity. Increased expression of exhaustion markers, especially in CAR7-NK cells, suggests that combining CAR-NK cells with immune checkpoint inhibitors might improve anti-tumour outcomes. These findings provide crucial insights for developing CAR-NK cell products for clinical applications. | [
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] | 2024-06-04 | 52 | 38830795 | [
"NK cells",
"NK cell expansion ability",
"NK",
"CAR constructs",
"CAR-NK cell products",
"CAR-NK cells",
"OX40 co-stimulatory domain",
"CAR7-NK cells",
"anti-tumour outcomes",
"CAR5-NK cells",
"CAR",
"CAR1-NK cells",
"CAR-T cells",
"CD8 TMD-OX40 CD- FcεRIγ SD",
"TMD",
"SD)-",
"Superior survival rates",
"CD8 TMD-CD3ζ",
"superior efficacy",
"immune checkpoint inhibitors",
"enhanced persistence",
"CD8 TMD-OX40 CD-CD3ζ 1-ITAM SD)-NK cells",
"crucial insights",
"CAR7-NK",
"CAR4-NK",
"the weakest anti-tumour activity",
"CAR1-, CAR2 (CD8 TMD- FcεRIγ SD)-, CAR3 (CD8 TMD-OX40 CD- CD3ζ SD)- and CAR4-NK cells",
"exhaustion markers",
"CAR5-NK",
"CAR7"
] | [] | 0 | 10.1111/cpr.13683 | [
"Wang",
"Li",
"Wang",
"Liu",
"Wang",
"Zhang",
"Xia",
"Zhang",
"Huang",
"Zhang",
"Zhao",
"Liu",
"Zhu",
"Qi",
"Zhu",
"Qian",
"Hu",
"Wang"
] | [
"Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.\nState Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.\nBeijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.\nUniversity of Chinese Academy of Sciences, Beijing, China.",
"Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.\nState Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.\nBeijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.\nUniversity of Chinese Academy of Sciences, Beijing, China.",
"State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.\nBeijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.\nUniversity of Chinese Academy of Sciences, Beijing, China.",
"State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.",
"State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.",
"State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.",
"Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.",
"State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.\nBeijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.\nUniversity of Chinese Academy of Sciences, Beijing, China.",
"State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.",
"Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.",
"State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.\nBeijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.\nGMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, China.",
"State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.",
"State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.",
"Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.",
"State Key Laboratory of Experimental Hematology & National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.\nCenter for Stem Cell Medicine & Department of Stem Cell and Regenerative Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.",
"Department of Hematology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang, Hangzhou, China.",
"Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.",
"State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.\nBeijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.\nUniversity of Chinese Academy of Sciences, Beijing, China."
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38827326 | 902 | Preclinical evaluation of cyclophosphamide and fludarabine combined with CD19 CAR-T in the treatment of B-cell hematologic malignancies | Chimeric antigen receptor T (CAR-T) cell therapy has achieved marked therapeutic success in ameliorating hematological malignancies. However, there is an extant void in the clinical guidelines concerning the most effective chemotherapy regimen prior to chimeric antigen receptor T (CAR-T) cell therapy, as well as the optimal timing for CAR-T cell infusion post-chemotherapy.
We employed cell-derived tumor xenograft (CDX) murine models to delineate the optimal pre-conditioning chemotherapy regimen and timing for CAR-T cell treatment. Furthermore, transcriptome sequencing was implemented to identify the therapeutic targets and elucidate the underlying mechanisms governing the treatment regimen.
Our preclinical
In summary, the present study offers critical clinical guidance and serves as an authoritative reference for the deployment of CD19 CAR-T cell therapy in the treatment of B-cell hematological malignancies. | [
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"Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China.",
"Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China.",
"Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China.",
"Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China.",
"Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China.\nScientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China.",
"Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China.\nScientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China.",
"Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China.",
"Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China.\nScientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China.",
"Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China.\nScientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China.",
"Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China."
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38825523 | 903 | [Development of novel bispecific antibody therapy for multiple myeloma]. | Over the past decade, new therapeutic modalities have markedly improved clinical outcomes for patients with multiple myeloma. Recently, immunotherapy using both bispecific antibodies (BsAb) and chimeric antigen receptor T cells (CAR-T cells) has induced further anti-myeloma responses. Different agents must be combined to overcome the heterogeneity of myeloma cell clones, and new modalities for the treatment of refractory myeloma must also be developed to strengthen therapeutic effects. We have developed a novel BiTE (bispecific T-cell engager)-based modality, referred to as bridging-BiTE (B-BiTE). B-BiTE is able to bind to both an Fc domain of a human immunoglobulin G monoclonal antibody (mAb) and the human CD3 molecule. This enables rapid generation of a mAb/B-BiTE complex and safely induces dual-lymphoid activation of both human T cells and NK cells against myeloma cells. Importantly, sequential immunotherapy using two different mAb/B-BiTE complexes can produce deep and durable anti-myeloma responses. To further advance treatment of multiple myeloma, it is important to determine how to combine and sequence immunotherapy with other agents while considering management of unique adverse events caused by activated immune cells. | [
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] | 2024-06-03 | 1 | 38825523 | [
"myeloma cells",
"myeloma cell clones",
"chimeric antigen receptor T cells",
"NK cells",
"activated immune cells",
"new therapeutic modalities",
"multiple myeloma",
"BiTE",
"new modalities",
"refractory myeloma",
"further anti-myeloma responses",
"G monoclonal antibody",
"Different agents",
"unique adverse events",
"other agents",
"sequential immunotherapy",
"both human T cells",
"immunotherapy",
"therapeutic effects",
"deep and durable anti-myeloma responses",
"CAR-T cells",
"rapid generation",
"treatment",
"(bispecific T-cell engager)-based modality",
"mAb",
"a novel BiTE",
"B-BiTE",
"bridging-BiTE (B-BiTE",
"management",
"two different mAb/B-BiTE complexes"
] | [
"Bispecific antibody",
"Dual-lymphoid activation",
"Immunotherapy",
"Multiple myeloma"
] | 0 | 10.11406/rinketsu.65.428 | [
"Konishi",
"Ochi",
"Takenaka"
] | [
"Department of Hematology, Clinical Immunology and Infectious diseases, Ehime University Graduate School of Medicine.",
"Department of Hematology, Clinical Immunology and Infectious diseases, Ehime University Graduate School of Medicine.\nDivision of Immune Regulation, Proteo-Science Center, Ehime University.",
"Department of Hematology, Clinical Immunology and Infectious diseases, Ehime University Graduate School of Medicine."
] | [
"38825523"
] | [] | 5.179091 | 6.329619 |
38824567 | 904 | A new era of cancer immunotherapy: combining revolutionary technologies for enhanced CAR-M therapy. | Significant advancements have been made in the application of chimeric antigen receptor (CAR)-T treatment for blood cancers during the previous ten years. However, its effectiveness in treating solid tumors is still lacking, necessitating the exploration of alternative immunotherapies that can overcome the significant challenges faced by current CAR-T cells. CAR-based immunotherapy against solid tumors shows promise with the emergence of macrophages, which possess robust phagocytic abilities, antigen-presenting functions, and the ability to modify the tumor microenvironment and stimulate adaptive responses. This paper presents a thorough examination of the latest progress in CAR-M therapy, covering both basic scientific studies and clinical trials. This study examines the primary obstacles hindering the realization of the complete potential of CAR-M therapy, as well as the potential strategies that can be employed to overcome these hurdles. With the emergence of revolutionary technologies like in situ genetic modification, synthetic biology techniques, and biomaterial-supported gene transfer, which provide a wider array of resources for manipulating tumor-associated macrophages, we suggest that combining these advanced methods will result in the creation of a new era of CAR-M therapy that demonstrates improved efficacy, safety, and availability. | [
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"availability",
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10.1038/nm.4478 | [
"Li",
"Geng",
"Dong",
"Jin",
"Ying",
"Li",
"Shi"
] | [
"Key lab of Artificial Organs and Computational Medicine, Institute of Translational Medicine, Zhejiang Shuren University, Hangzhou, Zhejiang, 310015, China.\nDepartment of Immunology, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China.",
"Key lab of Artificial Organs and Computational Medicine, Institute of Translational Medicine, Zhejiang Shuren University, Hangzhou, Zhejiang, 310015, China.",
"Key lab of Artificial Organs and Computational Medicine, Institute of Translational Medicine, Zhejiang Shuren University, Hangzhou, Zhejiang, 310015, China.\nDepartment of Chemistry, The Chinese University of Hong Kong, Shatin, Hong Kong, China.",
"Hangzhou Institute of Medicine (HIM), Zhejiang Caner Hospital, Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China.",
"Hangzhou Institute of Medicine (HIM), Zhejiang Caner Hospital, Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China.",
"Department of Chemistry, The Chinese University of Hong Kong, Shatin, Hong Kong, China.",
"Key lab of Artificial Organs and Computational Medicine, Institute of Translational Medicine, Zhejiang Shuren University, Hangzhou, Zhejiang, 310015, China. [email protected]."
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38822527 | 905 | Bispecific antibodies and autologous chimeric antigen receptor T cell therapies for treatment of hematological malignancies. | In recent years, the therapeutic landscape for hematological malignancies has markedly advanced, particularly since the inaugural approval of autologous chimeric antigen receptor T cell (CAR-T) therapy in 2017 for relapsed/refractory acute lymphoblastic leukemia (ALL). Autologous CAR-T therapy involves the genetic modification of a patient's T cells to specifically identify and attack cancer cells, while bispecific antibodies (BsAbs) function by binding to both cancer cells and immune cells simultaneously, thereby triggering an immune response against the tumor. The subsequent approval of various CAR-T therapies and BsAbs have revolutionized the treatment of multiple hematological malignancies, highlighting high response rates and a subset of patients achieving prolonged disease control. This review explores the mechanisms underlying autologous CAR-T therapies and BsAbs, focusing on their clinical application in multiple myeloma, ALL, and non-Hodgkin lymphoma. We provide comprehensive insights into their individual efficacy, limitations concerning broad application, and the potential of combination therapies. These upcoming strategies aim to propel the field forward, paving the way for safer and more effective therapeutic interventions in hematological malignancies. | [
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38821728 | 906 | Impact of Previous Allogeneic Hematopoietic Stem Cell Transplantation on Chimeric Antigen Receptor (CAR) T Cell Treatment for Relapsed/Refractory Multiple Myeloma. | Anti-BCMA-directed chimeric antigen receptor (CAR) T cells are effective treatment for patients with refractory/relapsed multiple myeloma (RRMM). However, little is known about the impact of previous allogeneic hematopoietic stem cell transplantation (allo-HSCT) on lymphocyte collection for production of CAR T cells and subsequent treatment with CAR T cells.
We performed a retrospective analysis of cellular composition of lymphocyte collections, CAR T cell expansion and treatment outcomes of RRMM patients undergoing therapy with idecabtagene vicleucel (ide-cel) with and without history of allo-HSCT. 27 patients (11/27 female) with median age 63 (range 39-75) years were analyzed. Five patients (19%) had the history of allo-HSCT median of 5.5 years before ide-cel.
Prior to apheresis, the white blood cell, absolute lymphocyte counts, CD3+ cells and monocytes did not differ in patients with and without prior allo-HSCT. We also noticed no differences in the collected CD3+ yields or cellular compositions of lymphocyte collections. One year after ide-cel infusion, the progression-free survival and overall survival of patients with and without previous allo-HSCT did not differ with 60% and 45% respectively (P = .58) and 66.7% and 74% respectively (P = .84). The highest expansion of CAR T was detected between day 7 after infusion and showed no difference regarding previous allo-HSCT (P = .71). No graft-versus-host disease during the follow-up was detected.
Our data confirm that the treatment with ide-cel is feasible for patients with prior allo-HSCT. Furthermore, allo-HSCT did not influence cellular composition of lymphocyte collections, clinical outcome or in vivo expansion of ide-cel. | [
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] | 2024-06-01 | 1 | 38821728 | [
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] | [
"Allogeneic stem cell transplantation",
"Ide-cel"
] | 0 | 10.1016/j.clml.2024.05.006 | [
"Kirchberg",
"Fischer",
"Born",
"Brunner",
"Morgner",
"Fürst",
"Heyn",
"Bach",
"Brueckner",
"Jentzsch",
"Wang",
"Böttcher",
"Franke",
"Schrezenmeier",
"Platzbecker",
"Merz",
"Vučinić"
] | [
"Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Leipzig Medical Center, Leipzig, Germany; Comprehensive Cancer Center Central Germany, Leipzig, Jena, Germany.",
"Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Leipzig Medical Center, Leipzig, Germany; Comprehensive Cancer Center Central Germany, Leipzig, Jena, Germany.",
"Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Leipzig Medical Center, Leipzig, Germany; Comprehensive Cancer Center Central Germany, Leipzig, Jena, Germany.",
"Department of Internal Medicine IV, Hematology and Oncology, Martin Luther University Halle-Wittenberg, Halle, Germany.",
"Department of Internal Medicine IV, Hematology and Oncology, Martin Luther University Halle-Wittenberg, Halle, Germany.",
"Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service, Baden Wuerttemberg-Hessen, University Hospital Ulm, Ulm, Germany; Institute of Transfusion Medicine, University of Ulm, Ulm, Germany.",
"Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Leipzig Medical Center, Leipzig, Germany; Comprehensive Cancer Center Central Germany, Leipzig, Jena, Germany.",
"Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Leipzig Medical Center, Leipzig, Germany; Comprehensive Cancer Center Central Germany, Leipzig, Jena, Germany.",
"Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Leipzig Medical Center, Leipzig, Germany; Comprehensive Cancer Center Central Germany, Leipzig, Jena, Germany.",
"Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Leipzig Medical Center, Leipzig, Germany; Comprehensive Cancer Center Central Germany, Leipzig, Jena, Germany.",
"Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Leipzig Medical Center, Leipzig, Germany; Comprehensive Cancer Center Central Germany, Leipzig, Jena, Germany.",
"Department of Medicine III Hematology, Oncology and Palliative Care, University Hospital, Rostock, Germany.",
"Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Leipzig Medical Center, Leipzig, Germany; Comprehensive Cancer Center Central Germany, Leipzig, Jena, Germany.",
"Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service, Baden Wuerttemberg-Hessen, University Hospital Ulm, Ulm, Germany; Institute of Transfusion Medicine, University of Ulm, Ulm, Germany.",
"Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Leipzig Medical Center, Leipzig, Germany; Comprehensive Cancer Center Central Germany, Leipzig, Jena, Germany.",
"Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Leipzig Medical Center, Leipzig, Germany; Comprehensive Cancer Center Central Germany, Leipzig, Jena, Germany.",
"Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Leipzig Medical Center, Leipzig, Germany; Comprehensive Cancer Center Central Germany, Leipzig, Jena, Germany. Electronic address: [email protected]."
] | [
"38821728"
] | [] | 5.423347 | 5.590707 |
38819691 | 907 | Nanoinjection: A Platform for Innovation in Ex Vivo Cell Engineering. | ConspectusIn human cells, intracellular access and therapeutic cargo transport, including gene-editing tools (e.g., CRISPR-Cas9 and transposons), nucleic acids (e.g., DNA, mRNA, and siRNA), peptides, and proteins (e.g., enzymes and antibodies), are tightly constrained to ensure healthy cell function and behavior. This principle is exemplified in the delivery mechanisms of chimeric antigen receptor (CAR)-T cells for ex-vivo immunotherapy. In particular, the clinical success of CAR-T cells has established a new standard of care by curing previously incurable blood cancers. The approach involves the delivery, typically via the use of electroporation (EP) and lentivirus, of therapeutic CAR genes into a patient's own T cells, which are then engineered to express CARs that target and combat their blood cancer. But the key difficulty lies in genetically manipulating these cells without causing irreversible damage or loss of function─all the while minimizing complexities of manufacturing, safety concerns, and costs, and ensuring the efficacy of the final CAR-T cell product.Nanoinjection─the process of intracellular delivery using nanoneedles (NNs)─is an emerging physical delivery route that efficiently negotiates the plasma membrane of many cell types, including primary human T cells. It occurs with minimal perturbation, invasiveness, and toxicity, with high efficiency and throughput at high spatial and temporal resolutions. Nanoinjection promises greatly improved delivery of a broad range of therapeutic cargos with little or no damage to those cargos. A nanoinjection platform allows these cargos to function in the intracellular space as desired. The adaptability of nanoinjection platforms is now bringing major advantages in immunomodulation, mechanotransduction, sampling of cell states (nanobiopsy), controlled intracellular interrogation, and the primary focus of this account─intracellular delivery and its applications in ex vivo cell engineering.Mechanical nanoinjection typically exerts direct mechanical force on the cell membrane, offering a straightforward route to improve membrane perturbation by the NNs and subsequent transport of genetic cargo into targeted cell type (adherent or suspension cells). By contrast, electroactive nanoinjection is controlled by coupling NNs with an electric field─a new route for activating electroporation (EP) at the nanoscale─allowing a dramatic reduction of the applied voltage to a cell and so minimizing post-EP damage to cells and cargo, and overcoming many of the limitations of conventional bulk EP. Nanoinjection transcends mere technique; it is an approach to cell engineering ex vivo, offering the potential to endow cells with new, powerful features such as generating chimeric antigen receptor (CAR)-T cells for future CAR-T cell technologies.We first discuss the manufacturing of NN devices (Section 2), then delve into nanoinjection-mediated cell engineering (Section 3), nanoinjection mechanisms and interfacing methodologies (Section 4), and emerging applications in using nanoinjection to create functional CAR-T cells (Section 5). | [
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10.1172/JCI35798 | [
"Chen",
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"Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China.\nMonash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.",
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"Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.\nMelbourne Centre for Nanofabrication, Victorian Node of the Australian National Fabrication Facility, 151 Wellington Road, Clayton, VIC 3168, Australia.\nSchool of Medicine, Faculty of Health, Deakin University, Waurn Ponds, VIC 3216, Australia.\nInstitute for Frontier Materials, Deakin University, Geelong Waurn Ponds campus, VIC 3216, Australia.\nThe Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong Waurn Ponds Campus, Melbourne, VIC 3216, Australia."
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38819641 | 908 | Human 3D Ovarian Cancer Models Reveal Malignant Cell-Intrinsic and -Extrinsic Factors That Influence CAR T-cell Activity. | In vitro preclinical testing of chimeric antigen receptor (CAR) T cells is mostly carried out in monolayer cell cultures. However, alternative strategies are needed to take into account the complexity and the effects of the tumor microenvironment. Here, we describe the modulation of CAR T-cell activity by malignant cells and fibroblasts in human three-dimensional (3D) in vitro cell models of increasing complexity. In models combining mucin-1 (MUC1) and TnMUC1 CAR T cells with human high-grade serous ovarian cancer cell spheroids, malignant cell-intrinsic resistance to CAR T-cell killing was due to defective death receptor signaling involving TNFα. Adding primary human fibroblasts to spheroids unexpectedly increased the ability of CAR T cells to kill resistant malignant cells as CCL2 produced by fibroblasts activated CCR2/4+ CAR T cells. However, culturing malignant cells and fibroblasts in collagen gels engendered production of a dense extracellular matrix that impeded CAR T-cell activity in a TGFβ-dependent manner. A vascularized microfluidic device was developed that allowed CAR T cells to flow through the vessels and penetrate the gels in a more physiological way, killing malignant cells in a TNFα-dependent manner. Complex 3D human cell models may provide an efficient way of screening multiple cytotoxic human immune cell constructs while also enabling evaluation of mechanisms of resistance involving cell-cell and cell-matrix interactions, thus accelerating preclinical research on cytotoxic immune cell therapies in solid tumors. Significance: Three-dimensional in vitro models of increasing complexity uncover mechanisms of resistance to CAR T cells in solid tumors, which could help accelerate development of improved CAR T-cell constructs. | [
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"CAR T cells",
"malignant cells",
"TnMUC1 CAR T cells",
"resistant malignant cells",
"Complex 3D human cell models",
"cytotoxic immune cell therapies",
"monolayer cell cultures",
"multiple cytotoxic human immune cell constructs",
"fibroblasts activated CCR2/4+ CAR T cells",
"improved CAR T-cell constructs",
"CAR T-cell activity",
"CAR T-cell killing",
"primary human fibroblasts",
"human high-grade serous ovarian cancer cell spheroids",
"malignant cell-intrinsic resistance",
"cell-cell and cell-matrix interactions",
"increasing complexity uncover mechanisms",
"vitro cell models",
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"increasing complexity",
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"defective death receptor",
"models",
"collagen gels",
"resistance",
"preclinical research",
"mechanisms",
"alternative strategies",
"spheroids"
] | [] | 0 | 10.1158/0008-5472.CAN-23-3007 | [
"Joy",
"Malacrida",
"Laforêts",
"Kotantaki",
"Maniati",
"Manchanda",
"Annibaldi",
"Hopkins",
"Garrobo-Calleja",
"Gautrot",
"Balkwill"
] | [
"Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.",
"Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.",
"Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.",
"Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.",
"Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.",
"Wolfson Institute of Population Health, Cancer Research UK, Barts Centre, Queen Mary University of London, London, United Kingdom.\nDepartment of Gynaecological Oncology, Royal London Hospital, Barts Health NHS Trust, London, United Kingdom.\nDepartment of Health Services Research and Policy, London School of Hygiene and Tropical Medicine, London, United Kingdom.",
"Centre for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.",
"GlaxoSmithKline Medicines Research Centre, Stevenage, United Kingdom.",
"GlaxoSmithKline Medicines Research Centre, Stevenage, United Kingdom.",
"School of Engineering and Material Science, Centre for Bioengineering, Queen Mary University of London, London, United Kingdom.",
"Barts Cancer Institute, Queen Mary University of London, London, United Kingdom."
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] | [] | 9.305361 | 5.307925 |
38819365 | 909 | Prolonged cytopenias after immune effector cell therapy and lymphodepletion in patients with leukemia, lymphoma and solid tumors. | The success of chimeric antigen receptor (CAR) T-cell therapy in treating B-cell malignancies has led to the evaluation of CAR T-cells targeting a variety of other malignancies. Although the efficacy of CAR T-cells is enhanced when administered post-lymphodepleting chemotherapy, this can trigger bone marrow suppression and sustained cytopenia after CD19.CAR T-cell therapy. Additionally, systemic inflammation associated with CAR T-cell activity may contribute to myelosuppression. Cytopenias, such as neutropenia and thrombocytopenia, elevate the risk of severe infections and bleeding, respectively. However, data on the incidence of prolonged cytopenias after immune effector therapy in the solid tumor context remain limited.
We compared the incidence of prolonged cytopenias after immune effector therapy including genetically modified T-cells, virus-specific T-cells (VSTs) and NKT-cells, as well non-gene-modified VSTs for leukemia, lymphoma, and solid tumors (ST) to identify associated risk factors.
A retrospective analysis was conducted of 112 pediatric and adult patients with relapsed and/or refractory cancers who received lymphodepleting chemotherapy followed by immune effector therapy. Patients treated with 13 distinct immune effector cell therapies through 11 single-center clinical trials and 2 commercial products over a 6-year period were categorized into 3 types of malignancies: leukemia, lymphoma and ST. We obtained baseline patient characteristics and adverse events data for each participant, and tracked neutrophil and platelet counts following lymphodepletion.
Of 112 patients, 104 (92.9%) experienced cytopenias and 88 (79%) experienced severe cytopenias. Patients with leukemia experienced significantly longer durations of severe neutropenia (median duration of 14 days) compared with patients with lymphoma (7 days) or ST (11 days) (P = 0.002). Patients with leukemia also had a higher incidence of severe thrombocytopenia (74.1%), compared with lymphoma (46%, P = 0.03) and ST (14.3%, P < 0.0001). Prolonged cytopenias were significantly associated with disease type (63% of patients with leukemia, 44% of patients with lymphoma, and 22.9% of patients with ST, P = 0.006), prior hematopoietic stem cell transplant (HSCT) (66.7% with prior HSCT versus 38.3% without prior HSCT, P = 0.039), and development of immune effector cell-associated neurotoxicity syndrome (ICANS) (75% with ICANS versus 38% without ICANS, P = 0.027). There was no significant association between prolonged cytopenias and cytokine release syndrome.
Immune effector recipients often experience significant cytopenias due to marrow suppression following lymphodepletion regardless of disease, but prolonged severe cytopenias are significantly less common after treatment of patients with lymphoma and solid tumors. | [
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] | 2024-05-31 | 30 | 38819365 | [
"prolonged severe cytopenias",
"immune effector therapy",
"severe cytopenias",
"prolonged cytopenias",
"prior hematopoietic stem cell transplant",
"experienced cytopenias",
"significant cytopenias",
"baseline patient characteristics",
"Patients",
"patients",
"immune effector cell-associated neurotoxicity syndrome",
"cytopenia",
"Prolonged cytopenias",
"severe thrombocytopenia",
"severe neutropenia",
"Immune effector recipients",
"CAR T-cell activity",
"associated risk factors",
"solid tumors",
"post-lymphodepleting chemotherapy",
"CAR T-cells",
"CD19.CAR T-cell therapy",
"severe infections",
"bone marrow suppression",
"lymphoma",
"treating B-cell malignancies",
"prior HSCT",
"marrow suppression",
"disease type",
"adverse events data"
] | [
"CAR T cells",
"cytopenia",
"hematologic toxicity",
"immune effector cells"
] | 0 | 10.1016/j.jcyt.2024.04.075 | [
"Miller",
"Daum",
"Wang",
"Wu",
"Tat",
"Pfeiffer",
"Navai",
"Heczey",
"Hegde",
"Ahmed",
"Whittle",
"Hill",
"Martinez",
"Krance",
"Ramos",
"Rouce",
"Lulla",
"Heslop",
"Omer",
"Shekar"
] | [
"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA.",
"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dell Medical School, University of Texas at Austin, Austin, TX, USA.",
"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA.",
"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA.",
"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA.",
"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA; Department of Pediatrics, Division of Hematology/Oncology, Washington University School of Medicine, St. Louis, MO, USA.",
"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA.",
"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA.",
"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA.",
"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.",
"Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA.",
"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA.",
"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA.",
"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA.",
"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA.",
"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA.",
"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA.",
"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA.",
"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA.",
"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA. Electronic address: [email protected]."
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38819362 | 910 | Enrichment of T-lymphocytes from leukemic blood using inertial microfluidics toward improved chimeric antigen receptor-T cell manufacturing. | Chimeric antigen receptor cell therapy is a successful immunotherapy for the treatment of blood cancers. However, hurdles in their manufacturing remain including efficient isolation and purification of the T-cell starting material. Herein, we describe a one-step separation based on inertial spiral microfluidics for efficient enrichment of T-cells in B-cell acute lymphoblastic leukemia (ALL) and B-cell chronic lymphocytic leukemia patient's samples. In healthy donors used to optimize the process, the lymphocyte purity was enriched from 65% (SD ± 0.2) to 91% (SD ± 0.06) and T-cell purity was enriched from 45% (SD ± 0.1) to 73% (SD ± 0.02). Leukemic samples had higher starting B-cells compared to the healthy donor samples. Efficient enrichment and recovery of lymphocytes and T-cells were achieved in ALL samples with B-cells, monocytes and leukemic blasts depleted by 80% (SD ± 0.09), 89% (SD ± 0.1) and 74% (SD ± 0.09), respectively, and a 70% (SD ± 0.1) T-cell recovery. Chronic lymphocytic leukemia samples had lower T-cell numbers, and the separation process was less efficient compared to the ALL. This study demonstrates the use of inertial microfluidics for T-cell enrichment and depletion of B-cell blasts in ALL, suggesting its potential to address a key bottleneck of the chimeric antigen receptor-T manufacturing workflow. | [
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] | 2024-05-31 | 1 | 38819362 | [
"Chimeric antigen receptor cell therapy",
"SD ±",
"Chronic lymphocytic leukemia samples",
"Efficient enrichment",
"efficient enrichment",
"B-cell acute lymphoblastic leukemia",
"inertial spiral microfluidics",
"lower T-cell numbers",
"Leukemic samples",
"T-cell enrichment",
"efficient isolation",
"higher starting B-cells",
"inertial microfluidics",
"B-cell blasts",
"T-cell purity",
"B-cell chronic lymphocytic leukemia patients samples",
"T-cells",
"B-cells",
"SD",
"leukemic blasts",
"healthy donors",
"the T-cell starting material",
"SD ± 0.1) T-cell recovery",
"blood cancers",
"lymphocytes",
"the chimeric antigen receptor-T manufacturing workflow",
"the healthy donor samples",
"ALL",
"purification",
"recovery"
] | [
"CAR-T",
"acute lymphoblastic leukemia",
"manufacturing",
"microfluidic",
"phenotype",
"purification"
] | 0 | 10.1016/j.jcyt.2024.05.005 | [
"Elsemary",
"Maritz",
"Smith",
"Warkiani",
"Thierry"
] | [
"Future Industries Institute, University of South Australia Mawson Lakes Campus, Mawson Lakes, SA, Australia.",
"Future Industries Institute, University of South Australia Mawson Lakes Campus, Mawson Lakes, SA, Australia.",
"Future Industries Institute, University of South Australia Mawson Lakes Campus, Mawson Lakes, SA, Australia.",
"University of Technology Sydney, Ultimo, NSW, Australia.",
"Future Industries Institute, University of South Australia Mawson Lakes Campus, Mawson Lakes, SA, Australia. Electronic address: [email protected]."
] | [
"38819362"
] | [] | 8.346952 | 3.088325 |
38819280 | 911 | [Optimizing efficacy and security of CAR-T cells, and immune monitoring]. | The immune system plays a critical role in the control and eradication of tumors. A better understanding of the anti-tumor immune mechanisms over the last decade has led to the development of immunotherapies, including cellular therapies such as those using CAR-T cells. These therapies have been remarkably effective in hematological malignancies. However, their application to solid tumors requires some optimization. Many efforts are being made in this regard, both to increase the efficacy of CAR-T cells, and to make them more secure. For the former goal, there is a need for the identification of new targets, better activation strategies, or arming T cells in a way that makes them able to overcome intra-tumoral barriers. For the latter goal, dose adjustment, locoregional administration or use of suicide genes are currently investigated as ways to mitigate the risks of this therapy. Together, these adjustments will permit larger applicability of CAR-T cells, in anti-tumor immunity, but also in the context of auto-immune diseases or fibrolytic therapies.
Optimisation de l’efficacité et de la sécurité d’utilisation des lymphocytes CAR-T.
Le système immunitaire joue un rôle déterminant dans le contrôle et l’éradication des tumeurs. Une meilleure compréhension des mécanismes en jeu a permis le développement des immunothérapies, et notamment des thérapies par lymphocytes CAR-T. Ces thérapies ont montré une grande efficacité dans les maladies hématologiques, mais leur application aux tumeurs solides nécessite des optimisations pour améliorer leur efficacité et leur sécurité. Ces ajustements permettront une plus grande applicabilité des lymphocytes CAR-T, non seulement pour les traitements anti-tumoraux mais aussi pour le traitement de maladies auto-immunes ou fibreuses. | [
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] | 2024-05-31 | 1 | 38819280 | [
"anti-tumoraux mais",
"anti-tumor immunity",
"T cells",
"applicabilité des lymphocytes",
"et notamment des thérapies par",
"aussi pour le traitement de maladies",
"Une meilleure compréhension des mécanismes",
"mais leur application aux tumeurs",
"applicabilité des",
"montré une grande efficacité dans",
"intra-tumoral barriers",
"cellular therapies",
"fibrolytic therapies",
"des",
"non seulement pour les traitements",
"nécessite des optimisations pour améliorer",
"mais leur",
"Optimisation de l’efficacité",
"the anti-tumor immune mechanisms",
"better activation strategies",
"Ces ajustements permettront une",
"dose adjustment",
"CAR-T cells",
"solid tumors",
"locoregional administration",
"dans",
"suicide genes",
"new targets",
"leur efficacité",
"grande"
] | [] | 0 | 10.1051/medsci/2024058 | [
"Lew-Derivry",
"Lamrani",
"Alcantara",
"Alanio"
] | [
"AP-HP, service d'oncologie et d'hématologie pédiatrique, Hôpital A. Trousseau, Paris, France - Institut Curie, PSL University, Inserm U932, Immunité et cancer, Paris, France - Laboratoire d'immunologie clinique et d'immunomonitoring, Institut Curie, Paris, France - CellAction, Institut Curie, Suresnes, France.",
"Institut Curie, PSL University, Inserm U932, Immunité et cancer, Paris, France - Laboratoire d'immunologie clinique et d'immunomonitoring, Institut Curie, Paris, France - CellAction, Institut Curie, Suresnes, France.",
"CellAction, Institut Curie, Suresnes, France.",
"Institut Curie, PSL University, Inserm U932, Immunité et cancer, Paris, France - Laboratoire d'immunologie clinique et d'immunomonitoring, Institut Curie, Paris, France - CellAction, Institut Curie, Suresnes, France."
] | [
"38819280"
] | [] | 9.478539 | 3.995322 |
38819256 | 912 | Impact of scFv on Functionality and Safety of Third-Generation CD123 CAR T Cells. | Chimeric antigen receptor (CAR) T cells express an extracellular domain consisting of a single-chain fragment variable (scFv) targeting a surface tumor-associated antigen. scFv selection should involve safety profiling with evaluation of the efficacy/toxicity balance, especially when the target antigen also is expressed on healthy cells. Here, to assess differences in terms of efficacy and on-target/off-tumor effects, we generated five different CARs targeting CD123 by substituting only the scFv. In in vitro models, T cells engineered to express three of these five CD123 CARs were effectively cytotoxic on leukemic cells without increasing lysis of monocytes or endothelial cells. Using the IncuCyte system, we confirmed the low cytotoxicity of CD123 CAR T cells on endothelial cells. Hematotoxicity evaluation using progenitor culture and CD34 cell lysis showed that two of the five CD123 CAR T cells were less cytotoxic on hematopoietic stem cells. Using a humanized mouse model, we confirmed that CD123- cells were not eliminated by the CD123 CAR T cells. Two CD123 CAR T cells reduced tumor infiltration and increased the overall survival of mice in three in vivo models of blastic plasmacytoid dendritic cell neoplasm. In an aggressive version of this model, bulk RNA sequencing analysis showed that these CD123 CAR T cells upregulated genes associated with cytotoxicity and activation/exhaustion a few days after the injection. Together, these results emphasize the importance of screening different scFvs for the development of CAR constructs to support selection of cells with the optimal risk-benefit ratio for clinical development. | [
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] | 2024-05-31 | 1 | 38819256 | [
"CD123 CAR T cells",
"T cells",
"cells",
"CD123- cells",
"endothelial cells",
"leukemic cells",
"CD34 cell lysis",
"healthy cells",
"hematopoietic stem cells",
"blastic plasmacytoid dendritic cell neoplasm",
"Two CD123 CAR T cells",
"the CD123 CAR T cells",
"these CD123 CAR T cells",
"CD123",
"vivo models",
"CAR",
"vitro models",
"tumor infiltration",
"scFv selection",
"different scFvs",
"the five CD123 CAR T cells",
"tumor",
"clinical development",
"Hematotoxicity evaluation",
"efficacy",
"bulk RNA",
"target",
"safety profiling",
"cytotoxicity",
"progenitor culture"
] | [] | 0 | 10.1158/2326-6066.CIR-23-0548 | [
"Fredon",
"Poussard",
"Biichlé",
"Bonnefoy",
"Mantion",
"Seffar",
"Renosi",
"Bôle-Richard",
"Boidot",
"Chevrier",
"Anna",
"Loustau",
"Caumartin",
"Gonçalves-Venturelli",
"Robinet",
"Saas",
"Deconinck",
"Daguidau",
"Roussel",
"Godet",
"Adotévi",
"Angelot-Delettre",
"Galaine",
"Garnache-Ottou"
] | [
"INSERM, EFS BFC, UMR1098-RIGHT, University of Franche-Comté, Besançon, France.",
"INSERM, EFS BFC, UMR1098-RIGHT, University of Franche-Comté, Besançon, France.",
"INSERM, EFS BFC, UMR1098-RIGHT, University of Franche-Comté, Besançon, France.",
"INSERM, EFS BFC, UMR1098-RIGHT, University of Franche-Comté, Besançon, France.",
"INSERM, EFS BFC, UMR1098-RIGHT, University of Franche-Comté, Besançon, France.",
"INSERM, EFS BFC, UMR1098-RIGHT, University of Franche-Comté, Besançon, France.\nMedical Oncology Department, CHU, Besançon, France.",
"INSERM, EFS BFC, UMR1098-RIGHT, University of Franche-Comté, Besançon, France.\nMolecular Onco-Hematology Laboratory, CHU, Besançon, France.",
"FC Innov', Bionovéo, Besançon, France.",
"Department of Tumor Biology and Pathology, Molecular Biology Unit, Georges-François Leclerc Center, Dijon, France.\nICMUB UMR CNRS 6302, Dijon, France.",
"Department of Tumor Biology and Pathology, Molecular Biology Unit, Georges-François Leclerc Center, Dijon, France.",
"Preclinical Department, Invectys, Paris, France.\nMolecular Virology and Vaccinology Unit, Pasteur Institute, Paris, France.",
"Preclinical Department, Invectys, Paris, France.",
"Preclinical Department, Invectys, Paris, France.",
"INSERM, EFS BFC, UMR1098-RIGHT, University of Franche-Comté, Besançon, France.\nLymphobank S.A.S.U, Besançon, France.",
"Lymphobank S.A.S.U, Besançon, France.",
"INSERM, EFS BFC, UMR1098-RIGHT, University of Franche-Comté, Besançon, France.",
"INSERM, EFS BFC, UMR1098-RIGHT, University of Franche-Comté, Besançon, France.\nHematology Department, CHU, Besançon, France.",
"INSERM, EFS BFC, UMR1098-RIGHT, University of Franche-Comté, Besançon, France.\nHematology Department, CHU, Besançon, France.",
"INSERM, EFS BFC, UMR1098-RIGHT, University of Franche-Comté, Besançon, France.\nHematology Department, CHU, Besançon, France.",
"INSERM, EFS BFC, UMR1098-RIGHT, University of Franche-Comté, Besançon, France.",
"INSERM, EFS BFC, UMR1098-RIGHT, University of Franche-Comté, Besançon, France.\nMedical Oncology Department, CHU, Besançon, France.",
"INSERM, EFS BFC, UMR1098-RIGHT, University of Franche-Comté, Besançon, France.",
"INSERM, EFS BFC, UMR1098-RIGHT, University of Franche-Comté, Besançon, France.",
"INSERM, EFS BFC, UMR1098-RIGHT, University of Franche-Comté, Besançon, France.\nHematology and Cellular Immunology Laboratory, CHU, Besançon, France."
] | [
"38819256"
] | [] | 8.422297 | 5.115399 |
38817602 | 913 | The role and novel use of natural killer cells in graft-versus-leukemia reactions after allogeneic transplantation. | Allogeneic hematopoietic cell transplantation (HCT) has transformed over the past several decades through enhanced supportive care, reduced intensity conditioning (RIC), improved human leukocyte antigen (HLA) typing, and novel graft-versus-host disease (GVHD)-prevention and treatment strategies. Most notably, the implementation of post-transplantation cyclophosphamide (PTCy) has dramatically increased the safety and availability of this life-saving therapy. Given reductions in nonrelapse mortality (NRM) with these advances, the HCT community has placed even greater emphasis on developing ways to reduce relapse - the leading cause of death after HCT. When using RIC HCT, protection from relapse relies predominantly on graft-versus-leukemia (GVL) reactions. Donor lymphocyte infusion (DLI), adoptive cellular therapy, checkpoint inhibition, and post-HCT maintenance strategies represent approaches under study that aim to augment or synergize with the GVL effects of HCT. Optimizing donor selection algorithms to leverage GVL represents another active area of research. Many of these strategies seek to harness the effects of T cells, which for decades were felt to be the primary mediators of GVL and the focus of investigation in relapse reduction. However, there is growing interest in capitalizing on the ability of natural killer (NK) cells to yield potent anti-tumor effects. A potential advantage of NK cell-based approaches over T cell-mediated is the potential to reduce NRM in addition to relapse. By decreasing infection, without increasing the risk of GVHD, NK cells may mitigate NRM, while still yielding relapse reduction through identification and clearance of cancer cells. Most T cell-focused relapse-prevention strategies must weigh the benefits of relapse reduction against the increased risk of NRM from GVHD. In contrast, NK cells have the potential to reduce both, potentially tipping the scales significantly in favor of survival. Here, we will review the role of NK cells in GVL, optimization of NK cell match or mismatch, and burgeoning areas of research in NK cell therapy such as adoptive transfer and chimeric antigen receptor (CAR) NK cells. | [
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] | [] | 11.525289 | 5.888865 |
38816881 | 914 | CRISPR/Cas-based CAR-T cells: production and application. | Chimeric antigen receptor T cell (CAR-T) therapy has revolutionized the treatment approach for cancer, autoimmune disease, and heart disease. The integration of CAR into T cells is typically facilitated by retroviral or lentiviral vectors. However, the random insertion of CARs can lead to issues like clonal expansion, oncogenic transformation, variegated transgene expression, and transcriptional silencing. The advent of precise gene editing technology, like Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), allows for controlled and precise genome modification, facilitating the translation of CAR-T research to the clinical applications. This review aims to provide a comprehensive analysis of the application of CRISPR gene editing techniques in the context of precise deletion and insertion methodologies, with a specific focus on their potential for enhancing the development and utilization of CAR-T cell therapy. | [
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] | [
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10.1038/s41422-022-00721-y | [
"Song",
"Zhang",
"Xu",
"Shi",
"Jing",
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] | [
"Department of Surgical Oncology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, No. 261, Huansha Road, Shangcheng district, Hangzhou 310006, Zhejiang, P. R. China.",
"Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.",
"Department of Respiratory Medicine, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu City, China.",
"Department of Respiratory Medicine, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu City, China.",
"Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.",
"Department of Surgical Oncology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, No. 261, Huansha Road, Shangcheng district, Hangzhou 310006, Zhejiang, P. R. China. [email protected].\nThe Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang, China. [email protected]."
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38814397 | 915 | Electroporation of mRNA as a Universal Technology Platform to Transfect a Variety of Primary Cells with Antigens and Functional Proteins. | Electroporation (EP) of mRNA into human cells is a broadly applicable method to transiently express proteins of choice in a variety of different cell types. We have spent more than two decades to optimize and adapt this method, first for antigen-loading of dendritic cells (DCs) and subsequently for T cells, B cells, bulk PBMCs, and several cell lines. In this regard, antigens were introduced, processed, and presented in context of MHC class I and II. Next to that, functional proteins like adhesion receptors, T-cell receptors (TCRs), chimeric antigen receptors (CARs), constitutively active signal transducers (i.e. caIKK), and others were successfully expressed. We have also established this protocol under full GMP compliance as part of a manufacturing license to produce mRNA-electroporated DCs and mRNA-electroporated T cells for therapeutic applications in clinical trials. Therefore, we here want to share our universal mRNA electroporation protocol and the experience we have gathered with this method. The advantages of the transfection method presented here are: (1) easy adaptation to different cell types; (2) scalability from 10 | [
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38814230 | 916 | Recent advances in immunotherapy in cancer treatment. | Immunotherapy has emerged as a transformative approach in cancer treatment, leveraging the body's own immune system to recognize and eradicate cancer cells. This review provides an overview of the recent advances and aspects in immunotherapy in cancer biology, from established therapies like checkpoint inhibitors and CAR-T cells to emerging innovative approaches and the challenges associated with their clinical translation. The exploration includes an examination of checkpoint inhibitors, elucidating the mechanisms behind programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors. Recent clinical successes and ongoing trials demonstrate the efficacy of checkpoint inhibitors across diverse malignancies, underscoring the potential for durable responses and improved patient outcomes. CAR-T cell therapy represents a groundbreaking avenue in immunotherapy, involving the genetic modification of a patient's T cells to express chimeric antigen receptors (CARs) for targeted cancer cell recognition. Furthermore, the review touches on the challenges associated with immunotherapy, including resistance mechanisms and adverse effects. Insightful discussions on overcoming resistance through combination therapies, adaptive treatment strategies, and emerging technologies underscore the ongoing efforts to enhance the long-term efficacy of immunotherapeutic interventions. In summary, this extensive review provides a comprehensive overview of recent advances in immunotherapy in cancer biology, highlighting the transformative impact of these therapies on patient outcomes, the challenges faced, and the promising directions for future research and clinical applications. | [
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] | 2024-05-30 | 1 | 38814230 | [
"cancer cells",
"targeted cancer cell recognition",
"programmed cell death protein",
"checkpoint inhibitors",
"cancer treatment",
"cancer biology",
"combination therapies",
"Recent clinical successes",
"established therapies",
"Immunotherapy",
"immunotherapy",
"emerging innovative approaches",
"recent advances",
"resistance mechanisms",
"improved patient outcomes",
"CAR-T cell therapy",
"emerging technologies",
"adaptive treatment strategies",
"patient outcomes",
"ongoing trials",
"chimeric antigen receptors",
"CAR-T cells",
"resistance",
"CARs",
"durable responses",
"diverse malignancies",
"immunotherapeutic interventions",
"Insightful discussions",
"adverse effects",
"future research and clinical applications"
] | [] | 0 | 10.14715/cmb/2024.70.5.13 | [
"Patel"
] | [
"Department of Clinical Biochemistry, College of Medicine, King Khalid University Abha, Kingdom of Saudi Arabia. [email protected]."
] | [
"38814230"
] | [] | 10.738269 | 4.193344 |
38813730 | 917 | Management of complications of chimeric antigen receptor T-cell therapy: a report by the European Society of Blood and Marrow Transplantation. | Chimeric antigen receptor (CAR) T cells are in standard clinical use to treat relapsed or refractory hematologic malignancies, such as non-Hodgkin lymphoma, multiple myeloma and acute lymphoblastic leukemia. Owing to the rapidly progressing field of CAR T-cell therapy and the lack of generally accepted treatment guidelines, we hypothesized significant differences between European centers in prevention, diagnosis and management of short- and long-term complications. To capture the current CAR T-cell management among European Society for Blood and Marrow Transplantation (EBMT) centers and to determine the medical need and specific areas for future clinical research the EBMT Transplant Complications Working Party performed a survey among 227 EBMT CAR T-cell centers. We received complete servey answers from 106 centers (47%) addressing questions in the areas of product selection, CAR T-cell logistics, management of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome as well as management in later phases including prolonged cytopenias. We identified common patterns in complication management, but also significant variety in clinical management of the centers in important aspects. Our results demonstrate a high medical need for treatment harmonization and future clinical research in the following areas: treatment of steroid-refractory and very severe cytokine release syndrome/neurotoxicity, treatment of cytopenia, early discharge and outpatient management, as well as immunoglobulin substitution. | [
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] | 2024-05-30 | 25 | 38813730 | [
"clinical management",
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"management",
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"CAR",
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"acute lymphoblastic leukemia",
"complete servey answers",
"significant variety",
"prolonged cytopenias",
"later phases",
"early discharge",
"Working Party",
"Marrow Transplantation"
] | [] | 0 | 10.3324/haematol.2023.284810 | [
"Penack",
"Peczynski",
"Boreland",
"Wolff",
"Moiseev",
"Schoemans",
"Koenecke",
"Graham",
"Peric"
] | [
"Medical Clinic, Department for Haematology, Oncology and Tumorimmunology, Charité Universitätsmedizin Berlin, Berlin, Germany; EBMT Transplant Complications Working Party, Department of Haematology, Saint Antoine Hospital; INSERM UMR-S 938, Sorbonne University, Paris. [email protected].",
"EBMT Transplant Complications Working Party, Department of Haematology, Saint Antoine Hospital; INSERM UMR-S 938, Sorbonne University, Paris, France; EBMT Paris study office, Department of Haematology, Saint Antoine Hospital; INSERM UMR-S 938, Sorbonne University, Paris.",
"EBMT Transplant Complications Working Party, Department of Haematology, Saint Antoine Hospital; INSERM UMR-S 938, Sorbonne University, Paris, France; EBMT Paris study office, Department of Haematology, Saint Antoine Hospital; INSERM UMR-S 938, Sorbonne University, Paris.",
"EBMT Transplant Complications Working Party, Department of Haematology, Saint Antoine Hospital; INSERM UMR-S 938, Sorbonne University, Paris, France; Dept. of Internal Medicine III, University Hospital Regensburg, Regensburg.",
"EBMT Transplant Complications Working Party, Department of Haematology, Saint Antoine Hospital; INSERM UMR-S 938, Sorbonne University, Paris, France; First Pavlov State Medical University of St Petersburg, St Petersburg, Russia.",
"EBMT Transplant Complications Working Party, Department of Haematology, Saint Antoine Hospital; INSERM UMR-S 938, Sorbonne University, Paris, France; Department of Hematology, University Hospitals Leuven and KU Leuven, Leuven.",
"EBMT Transplant Complications Working Party, Department of Haematology, Saint Antoine Hospital; INSERM UMR-S 938, Sorbonne University, Paris, France; Department of Haematology, Medical University Hannover, Hannover.",
"EBMT Transplant Complications Working Party, Department of Haematology, Saint Antoine Hospital; INSERM UMR-S 938, Sorbonne University, Paris, France; Comprehensive Cancer Centre,King's College London, London, UK.",
"EBMT Transplant Complications Working Party, Department of Haematology, Saint Antoine Hospital; INSERM UMR-S 938, Sorbonne University, Paris, France; Department of Haematology, University Hospital Centre Rijeka, Rijeka, Croatia."
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] | [] | 6.731836 | 4.086999 |
38813706 | 918 | LILRB4 represents a promising target for immunotherapy by dual targeting tumor cells and myeloid-derived suppressive cells in multiple myeloma. | Multiple myeloma (MM) remains an incurable hematologic malignancy. Despite tremendous advances in the treatment of this disease, about 10% of patients still have very poor outcomes with a median overall survival of less than 24 months. Our study aimed to underscore the critical mechanisms pertaining to rapid disease progression and provide novel therapeutic choices for these ultrahigh-risk patients. We utilized single-cell transcriptomic sequencing to dissect the characteristic bone marrow niche of patients who survived less than 2 years (EM24). Notably, enrichment of a LILRB4high pre-mature plasma-cell cluster was observed in EM24 patients compared to patients with durable remission. This cluster exhibited aggressive proliferation and a drug-resistance phenotype. High levels of LILRB4 promoted MM clonogenicity and progression. Clinically, high expression of LILRB4 was correlated with poor prognosis in both newly diagnosed MM patients and relapsed/ refractory MM patients. ATAC-sequencing analysis identified that pronounced chromosomal accessibility caused the elevation of LILRB4 on MM cells. CRISPR-Cas9 deletion of LILRB4 alleviated the growth of MM cells, inhibited the immunosuppressive function of myeloid-derived suppressive cells (MDSC), and further rescued T-cell dysfunction in the MM microenvironment. Greater infiltration of MDSC was observed in EM24 patients. We therefore generated an innovative T-cell receptor-based chimeric antigen receptor T cell, LILRB4-STAR-T. Cytotoxicity experiments demonstrated that LILRB4-STAR-T cells efficaciously eliminated tumor cells and impeded MDSC function. In conclusion, our study elucidates that LILRB4 is an ideal biomarker and promising immunotherapy target for high-risk MM. LILRB4-STAR-T-cell immunotherapy is promising against both tumor cells and the immunosuppressive tumor microenvironment in MM. | [
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"MDSC",
"LILRB4-STAR-T-cell immunotherapy",
"further rescued T-cell dysfunction",
"progression",
"both newly diagnosed MM patients"
] | [] | 0 | 10.3324/haematol.2024.285099 | [
"Gong",
"Sun",
"Liu",
"Sun",
"Fang",
"Yu",
"Sui",
"Xu",
"Wang",
"Feng",
"Lei",
"Rui",
"Liu",
"Zhao",
"An",
"Lin",
"Qiu",
"Hao"
] | [
"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; Tianjin Institutes of Health Science, Tianjin.",
"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; Tianjin Institutes of Health Science, Tianjin.",
"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; Tianjin Institutes of Health Science, Tianjin.",
"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; Tianjin Institutes of Health Science, Tianjin.",
"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; Tianjin Institutes of Health Science, Tianjin.",
"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; Tianjin Institutes of Health Science, Tianjin.",
"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; Tianjin Institutes of Health Science, Tianjin.",
"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; Tianjin Institutes of Health Science, Tianjin.",
"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; Tianjin Institutes of Health Science, Tianjin.",
"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; Tianjin Institutes of Health Science, Tianjin.",
"BriSTAR Immunotech Biotechnology Co. Ltd., Beijing.",
"BriSTAR Immunotech Biotechnology Co. Ltd., Beijing.",
"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; Tianjin Institutes of Health Science, Tianjin.",
"Department of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing.",
"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; Tianjin Institutes of Health Science, Tianjin.",
"Department of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing. [email protected].",
"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; Tianjin Institutes of Health Science, Tianjin. [email protected].",
"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; Tianjin Institutes of Health Science, Tianjin. [email protected]."
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38812569 | 919 | CXCL10 and IL15 co-expressing chimeric antigen receptor T cells enhance anti-tumor effects in gastric cancer by increasing cytotoxic effector cell accumulation and survival. | Chimeric antigen receptor (CAR) T cells have demonstrated outstanding therapeutic success in hematological malignancies. Yet, their efficacy against solid tumors remains constrained due to inadequate infiltration of cytotoxic T and CAR-T cells in the tumor microenvironment (TME), a factor correlated with poor prognosis in patients with solid tumors. To overcome this limitation, we engineered CAR-T cells to secrete CXCL10 and IL15 (10 × 15 CAR-T), which sustain T cell viability and enhance their recruitment, thereby amplifying the long-term cytotoxic capacity of CAR-T cells in vitro. In a xenograft model employing NUGC4-T21 cells, mice receiving 10 × 15 CAR-T cells showed superior tumor reduction and extended survival rates compared to those treated with second-generation CAR-T cells. Histopathological evaluations indicated a pronounced increase in cytotoxic T cell accumulation in the TME post 10 × 15 CAR-T cell treatment. Therefore, the synergistic secretion of CXCL10 and IL15 in these CAR-T cells enhances T cell recruitment and adaptability within tumor tissues, improving tumor control. This approach may offer a promising strategy for advancing CAR-T therapies in the treatment of solid tumors. | [
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] | [
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10.1186/s12964-023-01354-3 | [
"Nie",
"Song",
"Hu",
"Zu",
"Zhang",
"Chen",
"Ma",
"Zhou",
"Jiao"
] | [
"PLA Medical School, Beijing, China.\nResearch and Development Department, Beijing DCTY Biotech Co. LTD, Beijing, China.\nDepartment of Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.",
"Research and Development Department, Beijing DCTY Biotech Co. LTD, Beijing, China.",
"Research and Development Department, Beijing DCTY Biotech Co. LTD, Beijing, China.",
"Department of Functional Neurosurgery, Capital Medical University, Beijing, China.\nDepartment of Functional Neurosurgery, Xuanwu Hospital Capital Medical University, Beijing, China.",
"Research and Development Department, Beijing DCTY Biotech Co. LTD, Beijing, China.",
"Research and Development Department, Beijing DCTY Biotech Co. LTD, Beijing, China.",
"Research and Development Department, Beijing DCTY Biotech Co. LTD, Beijing, China.",
"Research and Development Department, Beijing DCTY Biotech Co. LTD, Beijing, China.",
"Department of Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China."
] | [
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] | [] | 9.563446 | 5.626837 |
38811838 | 920 | In silico study of heterogeneous tumour-derived organoid response to CAR T-cell therapy. | Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapy for treating cancers. This method consists in modifying the patients' T-cells to directly target antigen-presenting cancer cells. One of the barriers to the development of this type of therapies, is target antigen heterogeneity. It is thought that intratumour heterogeneity is one of the leading determinants of therapeutic resistance and treatment failure. While understanding antigen heterogeneity is important for effective therapeutics, a good therapy strategy could enhance the therapy efficiency. In this work we introduce an agent-based model (ABM), built upon a previous ABM, to rationalise the outcomes of different CAR T-cells therapies strategies over heterogeneous tumour-derived organoids. We found that one dose of CAR T-cell therapy should be expected to reduce the tumour size as well as its growth rate, however it may not be enough to completely eliminate it. Moreover, the amount of free CAR T-cells (i.e. CAR T-cells that did not kill any cancer cell) increases as we increase the dosage, and so does the risk of side effects. We tested different strategies to enhance smaller dosages, such as enhancing the CAR T-cells long-term persistence and multiple dosing. For both approaches an appropriate dosimetry strategy is necessary to produce "effective yet safe" therapeutic results. Moreover, an interesting emergent phenomenon results from the simulations, namely the formation of a shield-like structure of cells with low antigen expression. This shield turns out to protect cells with high antigen expression. Finally we tested a multi-antigen recognition therapy to overcome antigen escape and heterogeneity. Our studies suggest that larger dosages can completely eliminate the organoid, however the multi-antigen recognition increases the risk of side effects. Therefore, an appropriate small dosages dosimetry strategy is necessary to improve the outcomes. Based on our results, it is clear that a proper therapeutic strategy could enhance the therapies outcomes. In that direction, our computational approach provides a framework to model treatment combinations in different scenarios and to explore the characteristics of successful and unsuccessful treatments. | [
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10.1158/0008-5472.CAN-17-2006 | [
"Luque",
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] | [
"Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, EH16 4UU, UK. [email protected].",
"Instituto de Física de Líquidos y Sistemas Biológicos, Consejo Nacional de Investigaciones Científicas y Técnicas, 1900, La Plata, Argentina.\nDepartamento de Ingeniería Mecánica, Universidad Tecnológica Nacional, Facultad Regional La Plata, 1900, La Plata, Argentina.",
"Hospital General Universitario Gregorio Marañón, 28007, Madrid, Spain.",
"Instituto de Química Física Blas Cabrera, Consejo Superior de Investigaciones Científicas, 28006, Madrid, Spain."
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] | 2024-05-30 | 1 | 38811365 | [] | [] | 0 | 10.1002/cncr.35360 | [
"Nierengarten"
] | [
null
] | [
"38811365"
] | [] | 32.971226 | 7.497465 |
38810569 | 922 | Advancing autoimmune Rheumatic disease treatment: CAR-T Cell Therapies - Evidence, Safety, and future directions. | Despite advancements in managing autoimmune rheumatic diseases (ARDs) with existing treatments, many patients still encounter challenges such as inadequate responses, difficulty in maintaining remission, and side effects. Chimeric Antigen Receptor (CAR) T-cell therapy, originally developed for cancer, has now emerged as a promising option for cases of refractory ARDs.
A search of the literature was conducted to compose a narrative review exploring the current evidence, potential safety, limitations, potential modifications, and future directions of CAR-T cells in ARDs.
CAR-T cell therapy has been administered to patients with refractory ARDs, including systemic lupus erythematosus, antisynthetase syndrome, and systemic sclerosis, demonstrating significant improvement. Notable responses include enhanced clinical symptoms, reduced serum autoantibody titers, and sustained remissions in disease activity. Preclinical and in vitro studies using both animal and human samples also support the efficacy and elaborate on potential mechanisms of CAR-T cells against antineutrophil cytoplasmic antibody-associated vasculitis and rheumatoid arthritis. While cautious monitoring of adverse events, such as cytokine release syndrome, is crucial, the therapy appears to be highly tolerable. Nevertheless, challenges persist, including cost, durability due to potential CAR-T cell exhaustion, and manufacturing complexities, urging the development of innovative solutions to further enhance CAR-T cell therapy accessibility in ARDs.
CAR-T cell therapy for refractory ARDs has demonstrated high effectiveness. While no significant warning signs are currently reported, achieving a balance between therapeutic efficacy and safety is vital in adapting CAR-T cell therapy for ARDs. Moreover, there is significant potential for technological advancements to enhance the delivery of this treatment to patients, thereby ensuring safer and more effective disease control for patients. | [
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] | 2024-05-30 | 1 | 38810569 | [
"refractory ARDs",
"CAR-T cell therapy accessibility",
"CAR-T cell therapy",
"potential CAR-T cell exhaustion",
"potential safety",
"ARDs",
"enhanced clinical symptoms",
"potential modifications",
"potential mechanisms",
"many patients",
"autoimmune rheumatic diseases",
"CAR-T cells",
"cytokine release syndrome",
"patients",
"disease activity",
"therapeutic efficacy",
"systemic lupus erythematosus",
"significant potential",
"serum autoantibody titers",
"antisynthetase syndrome",
"inadequate responses",
"existing treatments",
"systemic sclerosis",
"technological advancements",
"significant improvement",
"adverse events",
"Notable responses",
"CAR) T-cell therapy",
"remission",
"remissions"
] | [
"Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV)",
"Antisynthetase syndrome (ASS)",
"Autoimmune rheumatic diseases (ARDs)",
"Chimeric Antigen Receptor (CAR)-T Cell",
"Chimeric autoantibody receptor T (CAAR-T) cells",
"Cytokine release syndrome (CRS)",
"Immune effector cell associated neurotoxicity syndrome (ICANS)",
"Regulatory T cells (Treg) expressing CAR (CAR-Tregs)",
"Systemic lupus erythematosus (SLE)",
"Systemic sclerosis (SSc)"
] | 0 | 10.1016/j.semarthrit.2024.152479 | [
"Ohno",
"Nakamura"
] | [
"Department of Medicine, Division of Rheumatology, Queen's University, Kingston, Ontario, Canada; Department of Medicine, Okayama University, Okayama, Japan.",
"Department of Medicine, Division of Rheumatology, Queen's University, Kingston, Ontario, Canada; Translational Institute of Medicine, School of Medicine, Queen's University, Ontario, Canada; Rheumatology Clinic, Kingston Health Science Centre, Kingston, Ontario, Canada. Electronic address: [email protected]."
] | [
"38810569"
] | [] | 7.417852 | 4.320101 |
38809963 | 923 | Payload-delivering engineered γδ T cells display enhanced cytotoxicity, persistence, and efficacy in preclinical models of osteosarcoma. | T cell-based cancer immunotherapy has typically relied on membrane-bound cytotoxicity enhancers such as chimeric antigen receptors expressed in autologous αβ T cells. These approaches are limited by tonic signaling of synthetic constructs and costs associated with manufacturing. γδ T cells are an emerging alternative for cellular therapy, having innate antitumor activity, potent antibody-dependent cellular cytotoxicity, and minimal alloreactivity. We present an immunotherapeutic platform technology built around the innate properties of the Vγ9Vδ2 T cell, harnessing specific characteristics of this cell type and offering an allocompatible cellular therapy that recruits bystander immunity. We engineered γδ T cells to secrete synthetic tumor-targeting opsonins in the form of an scFv-Fc fusion protein and a mitogenic IL-15Rα-IL-15 fusion protein (stIL15). Using GD2 as a model antigen, we show that GD2-specific opsonin-secreting Vγ9Vδ2 T cells (stIL15-OPS-γδ T cells) have enhanced cytotoxicity and promote bystander activity of other lymphoid and myeloid cells. Secretion of stIL-15 abrogated the need for exogenous cytokine supplementation and further mediated activation of bystander natural killer cells. Compared with unmodified γδ T cells, stIL15-OPS-γδ T cells exhibited superior in vivo control of subcutaneous tumors and persistence in the blood. Moreover, stIL15-OPS-γδ T cells were efficacious against patient-derived osteosarcomas in animal models and in vitro, where efficacy could be boosted with the addition of zoledronic acid. Together, the data identify stIL15-OPS-γδ T cells as a candidate allogeneic cell therapy platform combining direct cytolysis with bystander activation to promote tumor control. | [
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] | 2024-05-29 | 1 | 38809963 | [
"γδ T cells",
"autologous αβ T cells",
"bystander natural killer cells",
"cellular therapy",
"T cell-based cancer immunotherapy",
"unmodified γδ T cells, stIL15-OPS-γδ T cells",
"bystander activity",
"bystander activation",
"a candidate allogeneic cell therapy platform",
"GD2-specific opsonin-secreting Vγ9Vδ2 T cells",
"stIL15-OPS-γδ T cells",
"tumor control",
"synthetic constructs",
"chimeric antigen receptors",
"subcutaneous tumors",
"the Vγ9Vδ2 T cell",
"other lymphoid and myeloid cells",
"exogenous cytokine supplementation",
"animal models",
"cytotoxicity",
"antitumor activity",
"this cell type",
"specific characteristics",
"potent antibody-dependent cellular cytotoxicity",
"vivo control",
"synthetic tumor-targeting opsonins",
"direct cytolysis",
"an allocompatible cellular therapy",
"zoledronic acid",
"membrane-bound cytotoxicity enhancers"
] | [] | 0 | 10.1126/scitranslmed.adg9814 | [
"Fowler",
"Barisa",
"Southern",
"Nattress",
"Hawkins",
"Vassalou",
"Kanouta",
"Counsell",
"Rota",
"Vlckova",
"Draper",
"De Mooij",
"Farkas",
"Brezovjakova",
"Baker",
"Scotlandi",
"Manara",
"Tape",
"Chester",
"Anderson",
"Fisher"
] | [
"UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research, 20 Guilford Street, WC1N 1DZ London, UK.",
"UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research, 20 Guilford Street, WC1N 1DZ London, UK.",
"UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research, 20 Guilford Street, WC1N 1DZ London, UK.",
"UCL Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, WC1E 6DD London, UK.",
"UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research, 20 Guilford Street, WC1N 1DZ London, UK.",
"UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research, 20 Guilford Street, WC1N 1DZ London, UK.",
"UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research, 20 Guilford Street, WC1N 1DZ London, UK.",
null,
"UCL Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, WC1E 6DD London, UK.",
"UCL Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, WC1E 6DD London, UK.",
"UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research, 20 Guilford Street, WC1N 1DZ London, UK.",
"UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research, 20 Guilford Street, WC1N 1DZ London, UK.",
"UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research, 20 Guilford Street, WC1N 1DZ London, UK.",
"UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research, 20 Guilford Street, WC1N 1DZ London, UK.",
"UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research, 20 Guilford Street, WC1N 1DZ London, UK.",
"IRCCS Istituto Ortopedico Rizzoli, Experimental Oncology Laboratory, Via di Barbiano 1/10, 40136 Bologna Italy.",
"IRCCS Istituto Ortopedico Rizzoli, Experimental Oncology Laboratory, Via di Barbiano 1/10, 40136 Bologna Italy.",
"UCL Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, WC1E 6DD London, UK.",
"UCL Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, WC1E 6DD London, UK.",
"UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research, 20 Guilford Street, WC1N 1DZ London, UK.",
"UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research, 20 Guilford Street, WC1N 1DZ London, UK."
] | [
"38809963"
] | [] | 10.255496 | 4.421488 |
38805637 | 924 | CD20-bispecific antibodies improve response to CD19-CAR T cells in lymphoma in vitro and CLL in vivo models. | Relapse after anti-CD19 chimeric antigen receptor (CD19-CAR) occurs in a substantial proportion of patients with lymphoid malignancies. We assessed the potential benefits of co-administering CD20-targeting bispecific antibodies (CD20-BsAbs) with CD19-CAR T cells with the aim of enhancing immunotherapeutic efficacy. Addition of CD20-BsAbs to cocultures of CD19-CARs and primary samples of B-cell malignancies, comprising malignant B cells and endogenous T cells, significantly improved killing of malignant cells and enhanced the expansion of both endogenous T cells and CD19-CAR T cells. In an immunocompetent mouse model of chronic lymphocytic leukemia, relapse after initial treatment response frequently occurred after CD19-CAR T-cell monotherapy. Additional treatment with CD20-BsAbs significantly enhanced the treatment response and led to improved eradication of malignant cells. Higher efficacy was accompanied by improved T-cell expansion with CD20-BsAb administration and led to longer survival with 80% of the mice being cured with no detectable malignant cell population within 8 weeks of therapy initiation. Collectively, our in vitro and in vivo data demonstrate enhanced therapeutic efficacy of CD19-CAR T cells when combined with CD20-BsAbs in B-cell malignancies. Activation and proliferation of both infused CAR T cells and endogenous T cells may contribute to improved disease control. | [
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] | 2024-05-28 | 1 | 38805637 | [
"endogenous T cells",
"malignant B cells",
"malignant cells",
"enhanced therapeutic efficacy",
"CD19-CAR T cells",
"both infused CAR T cells",
"initial treatment response",
"anti-CD19 chimeric antigen receptor",
"improved T-cell expansion",
"both endogenous T cells",
"no detectable malignant cell population",
"chronic lymphocytic leukemia",
"B-cell malignancies",
"immunotherapeutic efficacy",
"improved eradication",
"CD19-CAR T-cell monotherapy",
"Higher efficacy",
"Additional treatment",
"improved disease control",
"lymphoid malignancies",
"longer survival",
"CD19-CAR",
"primary samples",
"CD20-BsAbs",
"Relapse",
"relapse",
"CD20-BsAb administration",
"therapy initiation",
"vivo data",
"co"
] | [] | 0 | 10.1182/blood.2023022682 | [
"Brinkmann",
"Floerchinger",
"Schniederjohann",
"Roider",
"Coelho",
"Mack",
"Bruch",
"Liebers",
"Dötsch",
"Busch",
"Schmitt",
"Neumann",
"Roessner",
"Seiffert",
"Dietrich"
] | [
"Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany.\nMolecular Medicine Partnership Unit, Heidelberg, Germany.\nGenome Biology, European Molecular Biology Laboratory, Heidelberg, Germany.\nClinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center, Heidelberg, Germany.\nFaculty of Biosciences, University of Heidelberg, Heidelberg, Germany.",
"Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany.\nMolecular Genetics, German Cancer Research Center, Heidelberg, Germany.",
"Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany.\nMolecular Medicine Partnership Unit, Heidelberg, Germany.\nFaculty of Biosciences, University of Heidelberg, Heidelberg, Germany.\nDepartment of Hematology, Oncology and Clinical Immunology, University Hospital Düsseldorf, Düsseldorf, Germany.\nCenter for Integrated Oncology Aachen Bonn Cologne Düsseldorf, Düsseldorf, Germany.",
"Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany.\nMolecular Medicine Partnership Unit, Heidelberg, Germany.\nGenome Biology, European Molecular Biology Laboratory, Heidelberg, Germany.",
"Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany.\nMolecular Genetics, German Cancer Research Center, Heidelberg, Germany.",
"Molecular Genetics, German Cancer Research Center, Heidelberg, Germany.",
"Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany.\nMolecular Medicine Partnership Unit, Heidelberg, Germany.\nDepartment of Hematology, Oncology and Clinical Immunology, University Hospital Düsseldorf, Düsseldorf, Germany.\nCenter for Integrated Oncology Aachen Bonn Cologne Düsseldorf, Düsseldorf, Germany.",
"Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany.\nMolecular Medicine Partnership Unit, Heidelberg, Germany.\nDepartment of Hematology, Oncology and Clinical Immunology, University Hospital Düsseldorf, Düsseldorf, Germany.\nCenter for Integrated Oncology Aachen Bonn Cologne Düsseldorf, Düsseldorf, Germany.\nDepartment of Translational Medical Oncology, National Center for Tumor Diseases, Heidelberg, Germany.",
"Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany.",
"Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany.\nGerman Center for Infection Research, Partner Site Munich, Munich, Germany.",
"Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany.\nGerman Cancer Consortium and German Cancer Research Center/National Center for Tumor Diseases, Heidelberg, Germany.",
"Department of Hematology, Oncology and Clinical Immunology, University Hospital Düsseldorf, Düsseldorf, Germany.",
"Molecular Genetics, German Cancer Research Center, Heidelberg, Germany.",
"Molecular Genetics, German Cancer Research Center, Heidelberg, Germany.",
"Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany.\nMolecular Medicine Partnership Unit, Heidelberg, Germany.\nGenome Biology, European Molecular Biology Laboratory, Heidelberg, Germany.\nDepartment of Hematology, Oncology and Clinical Immunology, University Hospital Düsseldorf, Düsseldorf, Germany.\nCenter for Integrated Oncology Aachen Bonn Cologne Düsseldorf, Düsseldorf, Germany."
] | [
"38805637"
] | [] | 6.785907 | 5.436233 |
38804307 | 925 | Identification of a Fully Human Antibody VH Domain Targeting Anaplastic Lymphoma Kinase (ALK) with Applications in ALK-Positive Solid Tumor Immunotherapy. | The anaplastic lymphoma kinase (ALK, CD247) is a potential target for antibody-based therapy. However, no antibody-based therapeutics targeting ALK have entered clinical trials, necessitating the development of novel antibodies with unique therapeutic merits. Single-domain antibodies (sdAb) bear therapeutic advantages compared to the full-length antibody including deeper tumor penetration, cost-effective production and fast washout from normal tissues. In this study, we identified a human immunoglobulin heavy chain variable domain (VH domain) (VH20) from an in-house phage library. VH20 exhibits good developability and high specificity with no off-target binding to ~6000 human membrane proteins. VH20 efficiently bound to the glycine-rich region of ALK with an EC | [
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] | 2024-05-28 | 45 | 38804307 | [
"VH domain",
"ALK",
"deeper tumor penetration",
"unique therapeutic merits",
"therapeutic advantages",
"human membrane proteins",
"a human immunoglobulin heavy chain variable domain",
"fast washout",
"VH20",
"high specificity",
"clinical trials",
"good developability",
"Single-domain antibodies",
"normal tissues",
"antibody-based therapy",
"novel",
"CD247",
"sdAb",
"house",
"cost-effective production",
"a potential target",
"no antibody-based therapeutics",
"the full-length antibody",
"anaplastic",
"The anaplastic lymphoma kinase",
"EC",
"the glycine-rich region",
"the development",
"no off-target",
"this study"
] | [
"ALK",
"immunotherapy",
"phage display",
"single-domain antibodies"
] | 0 | 10.3390/antib13020039
10.1016/s0002-9440(10)65042-0
10.1038/sj.onc.1200849
10.1038/nrc3580
10.1038/nature07397
10.1016/j.ccr.2012.02.010
10.1615/critrevoncog.v17.i2.10
10.1038/nature07261
10.1158/1078-0432.ccr-14-1100
10.1074/jbc.m501972200
10.1038/onc.2011.647
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10.1371/journal.pone.0033581 | [
"Chen",
"Sun",
"Wang",
"Shin",
"Berrios",
"Mellors",
"Dimitrov",
"Li"
] | [
"Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA 15261, USA.",
"Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA 15261, USA.",
"Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.",
"Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA 15261, USA.",
"Department of Biological Sciences, University of Pittsburgh Kenneth P. Dietrich School of Arts and Sciences, Pittsburgh, PA 15260, USA.",
"Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA 15261, USA.",
"Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA 15261, USA.",
"Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA 15261, USA."
] | [
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] | [] | 6.099428 | 6.874934 |
38803489 | 926 | Case report: Donor-derived CLL-1 chimeric antigen receptor T-cell therapy for relapsed/refractory acute myeloid leukemia bridging to allogeneic hematopoietic stem cell transplantation after remission. | Explore the efficacy and safety of donor-derived CLL-1 chimeric antigen receptor T-cell therapy (CAR-T) for relapsed/refractory acute myeloid leukemia (R/R AML) bridging to allogeneic hematopoietic stem cell transplantation (allo-HSCT) after remission.
An adult R/R AML patient received an infusion of donor-derived CLL-1 CAR-T cells, and the conditioning regimen bridging to allo-HSCT was started immediately after remission on day 11 after CAR-T therapy upon transplantation. Then, routine post-HSCT monitoring of blood counts, bone marrow (BM) morphology, flow cytometry, graft-versus-host disease (GVHD) manifestations, and chimerism status were performed.
After CAR-T therapy, cytokine release syndrome was grade 1. On day 11 after CAR-T therapy, the BM morphology reached complete remission (CR), and the conditioning regimen bridging to allo-HSCT started. Leukocyte engraftment, complete donor chimerism, and platelet engraftment were observed on days +18, +23, and +26 post-allo-HSCT, respectively. The BM morphology showed CR and flow cytometry turned negative on day +23. The patient is currently at 4 months post-allo-HSCT with BM morphology CR, negative flow cytometry, complete donor chimerism, and no extramedullary relapse/GVHD.
Donor-derived CLL-1 CAR-T is an effective and safe therapy for R/R AML, and immediate bridging to allo-HSCT after remission may better improve the long-term prognosis of R/R AML. | [
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] | 2024-05-28 | 27 | 38803489 | [
"complete donor chimerism",
"BM morphology CR",
"complete remission",
"negative flow cytometry",
"flow cytometry",
"routine post-HSCT monitoring",
"days +18",
"hematopoietic stem cell transplantation",
"chimerism status",
"AML",
"BM",
"remission",
"day",
"days",
"+26 post-allo-HSCT",
"donor-derived CLL-1 chimeric antigen receptor T-cell therapy",
"CR",
"post-allo-HSCT",
"R/R AML",
"donor-derived CLL-1 CAR-T cells",
"cytokine release syndrome",
"platelet engraftment",
"CAR-T therapy",
"blood counts",
"bone marrow",
"Leukocyte engraftment",
"immediate bridging",
"CLL-1",
"An adult R/R AML patient",
"GVHD"
] | [
"C-type lectin-like molecule 1",
"acute myeloid leukemia",
"allogeneic hematopoietic stem cell transplantation",
"donor-derived chimeric antigen receptor T cells",
"relapsed/refractory"
] | 0 | 10.3389/fimmu.2024.1389227
10.1002/ajh.26822
10.1007/s00277-023-05406-z
10.1111/ejh.14140
10.1182/hematology.2020000134
10.1038/s41591-023-02754-1
10.3389/fimmu.2018.00227
10.1158/0008-5472.can-04-1659
10.1186/s13045-017-0553-5
10.1002/cyto.b.21540
10.1186/s12943-016-0571-x
10.1111/cas.12817
10.1186/s13045-019-0726-5
10.1136/jitc-2023-006857
10.1038/s41375-022-01703-0
10.1186/s13045-022-01308-1
10.3389/fimmu.2022.931452
10.1200/jco.21.00389
10.1111/bjh.17746
10.1016/j.critrevonc.2022.103607
10.2174/2589977515666230220092125
10.1002/ctm2.1043
10.3389/fimmu.2023.1145441
10.1080/2162402x.2023.2248826
10.1016/j.cell.2018.05.013
10.1038/s41375-021-01253-x
10.1016/j.ymthe.2017.05.024 | [
"Miao",
"Shuai",
"Han",
"Zhang",
"Liu",
"Yao",
"Wang",
"He",
"Chen",
"Fan",
"Chang",
"Su",
"Yi"
] | [
"Department of Hematology, People's Liberation Army The General Hospital of Western Theater Command, Sichuan Clinical Research Center for Hematological Disease, Branch of National Clinical Research Center for Hematological Disease, Chengdu, Sichuan, China.",
"Department of Hematology, People's Liberation Army The General Hospital of Western Theater Command, Sichuan Clinical Research Center for Hematological Disease, Branch of National Clinical Research Center for Hematological Disease, Chengdu, Sichuan, China.",
"Department of Hematology, People's Liberation Army The General Hospital of Western Theater Command, Sichuan Clinical Research Center for Hematological Disease, Branch of National Clinical Research Center for Hematological Disease, Chengdu, Sichuan, China.",
"Department of Hematology, People's Liberation Army The General Hospital of Western Theater Command, Sichuan Clinical Research Center for Hematological Disease, Branch of National Clinical Research Center for Hematological Disease, Chengdu, Sichuan, China.",
"Department of Hematology, People's Liberation Army The General Hospital of Western Theater Command, Sichuan Clinical Research Center for Hematological Disease, Branch of National Clinical Research Center for Hematological Disease, Chengdu, Sichuan, China.",
"Department of Hematology, People's Liberation Army The General Hospital of Western Theater Command, Sichuan Clinical Research Center for Hematological Disease, Branch of National Clinical Research Center for Hematological Disease, Chengdu, Sichuan, China.",
"Department of Hematology, People's Liberation Army The General Hospital of Western Theater Command, Sichuan Clinical Research Center for Hematological Disease, Branch of National Clinical Research Center for Hematological Disease, Chengdu, Sichuan, China.",
"Department of Hematology, People's Liberation Army The General Hospital of Western Theater Command, Sichuan Clinical Research Center for Hematological Disease, Branch of National Clinical Research Center for Hematological Disease, Chengdu, Sichuan, China.",
"Department of Hematology, People's Liberation Army The General Hospital of Western Theater Command, Sichuan Clinical Research Center for Hematological Disease, Branch of National Clinical Research Center for Hematological Disease, Chengdu, Sichuan, China.",
"Department of Hematology, People's Liberation Army The General Hospital of Western Theater Command, Sichuan Clinical Research Center for Hematological Disease, Branch of National Clinical Research Center for Hematological Disease, Chengdu, Sichuan, China.",
"Shanghai YaKe Biotechnology Ltd., Shanghai, China.\nEngineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China.",
"Department of Hematology, People's Liberation Army The General Hospital of Western Theater Command, Sichuan Clinical Research Center for Hematological Disease, Branch of National Clinical Research Center for Hematological Disease, Chengdu, Sichuan, China.",
"Department of Hematology, People's Liberation Army The General Hospital of Western Theater Command, Sichuan Clinical Research Center for Hematological Disease, Branch of National Clinical Research Center for Hematological Disease, Chengdu, Sichuan, China."
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] | [] | 6.489491 | 5.956862 |
38803454 | 927 | Remission after CAR T-cell therapy: Do lymphoma patients recover a normal life? | Chimeric antigen receptor T cells (CAR T cells) can induce prolonged remission in a substantial subset of patients with relapse/refractory lymphoma. However, little is known about patients' life after CAR T-cell therapy. We prospectively assessed the multidimensional recovery of lymphoma patients in remission, before leukapheresis, before CAR T-cell infusion, and 3, 6, and 12 months thereafter. Validated tools were used to measure lymphoma-related and global health-related quality of life (HRQoL; Functional Assessment of Cancer Therapy-Lymphoma [FACT-Lym] and EQ-5D-5L), cognitive complaint (FACT-Cognition), fatigue (FACIT-Fatigue subscale), psychological status (Hospital Anxiety and Depression Scale, Post-Traumatic Check List Scale), and sexuality (Relationship and Sexuality Scale). Beyond 12 months of remission, we also surveyed physical, professional, sexual, and general life status. At 3, 6, and 12 months, 53, 35, and 23 patients were evaluable, respectively. Improvement in lymphoma-related HRQoL was clinically relevant at 3, 6, and 12 months with a mean change from baseline of 10.9 (95% confidence interval [CI]: 5.8; 16.1), 12.2 (95% CI: 4.2; 20.1), and 11.72 (95% CI: 2.06; 21.38), respectively. Improvement in global HRQoL, fatigue, and anxiety was clinically relevant, but 20%-40% of patients experienced persistent fatigue, psychological distress, and cognitive complaints over time. Beyond 12 months after CAR T cells, 81.8% of 22 evaluable patients were satisfied with their daily life. Physical activity, professional, sexual, and global well-being had returned to prediagnosis levels in nearly half of the patients. We found an improvement in HRQoL after CAR T-cell therapy including anxiety, depression, sexual satisfaction, and general well-being. However, not all patients recover a "normal life." Further research is needed to determine which patients are at risk of quality-of-life impairment to improve recovery after CAR T-cell infusion. | [
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] | [] | 0 | 10.1002/hem3.72
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"Service d'Hématologie-CHU Pontchaillou, Department of Hematology University Hospital of Rennes Rennes France.",
"Service d'Hématologie-CHU Pontchaillou, Department of Hematology University Hospital of Rennes Rennes France.",
"Human and Social Sciences Department Leon Berard Center Lyon France.",
"Human and Social Sciences Department Leon Berard Center Lyon France.\nDepartment of Clinical Research and Innovation Leon Berard Center Lyon France.",
"Service d'Hématologie-CHU Pontchaillou, Department of Hematology University Hospital of Rennes Rennes France.",
"Service d'Hématologie-CHU Pontchaillou, Department of Hematology University Hospital of Rennes Rennes France.",
"Service d'Hématologie-CHU Pontchaillou, Department of Hematology University Hospital of Rennes Rennes France.",
"Service d'Hématologie-CHU Pontchaillou, Department of Hematology University Hospital of Rennes Rennes France.",
"Service d'Hématologie-CHU Pontchaillou, Department of Hematology University Hospital of Rennes Rennes France.",
"Service d'Hématologie-CHU Pontchaillou, Department of Hematology University Hospital of Rennes Rennes France.",
"Department of Hematology Cancer University Institute of Toulouse Oncopole Toulouse France.",
"Department of Hematology Cancer University Institute of Toulouse Oncopole Toulouse France.",
"Department of Physical and Rehabilitation Medicine University Hospital of Rennes Rennes France.",
"Department of Physical and Rehabilitation Medicine University Hospital of Rennes Rennes France.",
"Service d'Hématologie-CHU Pontchaillou, Department of Hematology University Hospital of Rennes Rennes France.\nUMR U1236, INSERM University of Rennes Rennes France.",
"Service d'Hématologie-CHU Pontchaillou, Department of Hematology University Hospital of Rennes Rennes France.\nUMR U1236, INSERM University of Rennes Rennes France.",
"Service d'Hématologie-CHU Pontchaillou, Department of Hematology University Hospital of Rennes Rennes France."
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38802346 | 928 | Prognostic impact of corticosteroid and tocilizumab use following chimeric antigen receptor T-cell therapy for multiple myeloma. | Despite being the mainstay of management for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), there is limited data regarding the impact of tocilizumab (TCZ) and corticosteroids (CCS) on chimeric antigen receptor (CAR) T-cell efficacy in multiple myeloma (MM). The present study aims to evaluate the prognostic impact of these immunosuppressants in recipients of BCMA- or GPRC5D-directed CAR T cells for relapsed/refractory MM. Our retrospective cohort involved patients treated with commercial or investigational autologous CAR T-cell products at a single institution from March 2017-March 2023. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), complete response rate (CRR), and overall survival (OS). In total, 101 patients (91% treated with anti-BCMA CAR T cells and 9% treated with anti-GPRC5D CAR T cells) were analyzed. Within 30 days post-infusion, 34% received CCS and 49% received TCZ for CRS/ICANS management. At a median follow-up of 27.4 months, no significant difference in PFS was observed between CCS and non-CCS groups (log-rank p = 0.35) or between TCZ and non-TCZ groups (log-rank p = 0.69). ORR, CRR, and OS were also comparable between evaluated groups. In our multivariable model, administering CCS with/without TCZ for CRS/ICANS management did not independently influence PFS (HR, 0.74; 95% CI, 0.36-1.51). These findings suggest that, among patients with relapsed/refractory MM, the timely and appropriate use of CCS or TCZ for mitigating immune-mediated toxicities does not appear to impact the antitumor activity and long-term outcomes of CAR T-cell therapy. | [
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"Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.\nDepartment of Medicine, Mount Sinai Morningside and West, Icahn School of Medicine at Mount Sinai, New York, NY, USA.",
"Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.",
"Department of Medicine, Myeloma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.\nDepartment of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.",
"Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.",
"Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.",
"Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.\nDepartment of Medicine, Myeloma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.",
"Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.\nDepartment of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.\nDepartment of Medicine, Weill Cornell Medicine, New York, NY, USA.",
"Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.\nDepartment of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.\nDepartment of Medicine, Weill Cornell Medicine, New York, NY, USA.",
"Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.\nDepartment of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.\nDepartment of Medicine, Weill Cornell Medicine, New York, NY, USA.",
"Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.\nDepartment of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.\nDepartment of Medicine, Weill Cornell Medicine, New York, NY, USA.",
"Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.\nDepartment of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.\nDepartment of Medicine, Weill Cornell Medicine, New York, NY, USA.",
"Department of Medicine, Myeloma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.\nDepartment of Medicine, Weill Cornell Medicine, New York, NY, USA.",
"Department of Medicine, Myeloma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.\nDepartment of Medicine, Weill Cornell Medicine, New York, NY, USA.",
"Department of Medicine, Myeloma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.\nDepartment of Medicine, Weill Cornell Medicine, New York, NY, USA.",
"Department of Medicine, Myeloma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.\nDepartment of Medicine, Weill Cornell Medicine, New York, NY, USA.",
"Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.\nDepartment of Medicine, Myeloma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.\nDepartment of Medicine, Weill Cornell Medicine, New York, NY, USA.",
"Department of Medicine, Myeloma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.\nDepartment of Medicine, Weill Cornell Medicine, New York, NY, USA.",
"Department of Medicine, Myeloma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.\nDepartment of Medicine, Weill Cornell Medicine, New York, NY, USA.",
"Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.\nDepartment of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.\nDepartment of Medicine, Weill Cornell Medicine, New York, NY, USA.",
"Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.\nDepartment of Medicine, Myeloma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.\nDepartment of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.\nDepartment of Medicine, Weill Cornell Medicine, New York, NY, USA.",
"Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].",
"Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].\nDepartment of Medicine, Myeloma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].\nDepartment of Medicine, Weill Cornell Medicine, New York, NY, USA. [email protected]."
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38800555 | 929 | Engineered CAR-T cells targeting the non-functional P2X purinoceptor 7 (P2X7) receptor as a novel treatment for ovarian cancer. | Recent studies have identified expression of the non-functional P2X7 (nfP2X7) receptor on various malignant cells including ovarian cancer, but not on normal cells, which makes it a promising tumour-associated antigen candidate for chimeric antigen receptor (CAR)-T-cell immunotherapies. In this study, we assessed the cytotoxic effects of nfP2X7-CAR-T cells on ovarian cancer using
We evaluated the effects of nfP2X7-CAR-T cells on ovarian cancer cell lines (SKOV-3, OVCAR3, OVCAR5), normal peritoneal cells (LP-9) and primary serous ovarian cancer cells derived from patient ascites
Our study found that nfP2X7-CAR-T cells were cytotoxic and significantly inhibited survival of OVCAR3, OVCAR5 and primary serous ovarian cancer cells compared with un-transduced CD3
This study demonstrates that nfP2X7-CAR-T cells have great potential to be developed as a novel immunotherapy for ovarian cancer. | [
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] | [
"3D‐spheroid",
"CAR‐T cells",
"explant assays",
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] | 0 | 10.1002/cti2.1512 | [
"Bandara",
"Niktaras",
"Willett",
"Chapman",
"Lokman",
"Macpherson",
"Napoli",
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] | [
"Molecular Immunology, Robinson Research Institute University of Adelaide Adelaide SA Australia.",
"Reproductive Cancer Research Group, Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute University of Adelaide Adelaide SA Australia.",
"Reproductive Cancer Research Group, Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute University of Adelaide Adelaide SA Australia.",
"Reproductive Cancer Research Group, Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute University of Adelaide Adelaide SA Australia.",
"Reproductive Cancer Research Group, Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute University of Adelaide Adelaide SA Australia.",
"Reproductive Cancer Research Group, Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute University of Adelaide Adelaide SA Australia.",
"Molecular Immunology, Robinson Research Institute University of Adelaide Adelaide SA Australia.",
"Molecular Immunology, Robinson Research Institute University of Adelaide Adelaide SA Australia.",
"Chemokine Biology Laboratory, Department of Molecular and Biomedical Science, School of Biological Sciences The University of Adelaide Adelaide SA Australia.",
"Molecular Immunology, Robinson Research Institute University of Adelaide Adelaide SA Australia.",
"Carina Biotech, Level 2 Innovation & Collaboration Centre Adelaide SA Australia.",
"Chemokine Biology Laboratory, Department of Molecular and Biomedical Science, School of Biological Sciences The University of Adelaide Adelaide SA Australia.\nCarina Biotech, Level 2 Innovation & Collaboration Centre Adelaide SA Australia.",
"Molecular Immunology, Robinson Research Institute University of Adelaide Adelaide SA Australia.",
"Reproductive Cancer Research Group, Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute University of Adelaide Adelaide SA Australia.\nDepartment of Gynaecological Oncology Royal Adelaide Hospital Adelaide SA Australia.",
"Reproductive Cancer Research Group, Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute University of Adelaide Adelaide SA Australia."
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38800372 | 930 | Beyond BCMA: the next wave of CAR T cell therapy in multiple myeloma. | Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment landscape of relapsed/refractory multiple myeloma. The current Food and Drug Administration approved CAR T cell therapies idecabtagene vicleucel and ciltacabtagene autoleucel both target B cell maturation antigen (BCMA), which is expressed on the surface of malignant plasma cells. Despite deep initial responses in most patients, relapse after anti-BCMA CAR T cell therapy is common. Investigations of acquired resistance to anti-BCMA CAR T cell therapy are underway. Meanwhile, other viable antigenic targets are being pursued, including G protein-coupled receptor class C group 5 member D (GPRC5D), signaling lymphocytic activation molecule family member 7 (SLAMF7), and CD38, among others. CAR T cells targeting these antigens, alone or in combination with anti-BCMA approaches, appear to be highly promising as they move from preclinical studies to early phase clinical trials. This review summarizes the current data with novel CAR T cell targets beyond BCMA that have the potential to enter the treatment landscape in the near future. | [
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38799440 | 931 | The synergistic immunotherapeutic impact of engineered CAR-T cells with PD-1 blockade in lymphomas and solid tumors: a systematic review. | Currently, therapies such as chimeric antigen receptor-T Cell (CAR-T) and immune checkpoint inhibitors like programmed cell death protein-1 (PD-1) blockers are showing promising results for numerous cancer patients. However, significant advancements are required before CAR-T therapies become readily available as off-the-shelf treatments, particularly for solid tumors and lymphomas. In this review, we have systematically analyzed the combination therapy involving engineered CAR-T cells and anti PD-1 agents. This approach aims at overcoming the limitations of current treatments and offers potential advantages such as enhanced tumor inhibition, alleviated T-cell exhaustion, heightened T-cell activation, and minimized toxicity. The integration of CAR-T therapy, which targets tumor-associated antigens, with PD-1 blockade augments T-cell function and mitigates immune suppression within the tumor microenvironment. To assess the impact of combination therapy on various tumors and lymphomas, we categorized them based on six major tumor-associated antigens: mesothelin, disialoganglioside GD-2, CD-19, CD-22, CD-133, and CD-30, which are present in different tumor types. We evaluated the efficacy, complete and partial responses, and progression-free survival in both pre-clinical and clinical models. Additionally, we discussed potential implications, including the feasibility of combination immunotherapies, emphasizing the importance of ongoing research to optimize treatment strategies and improve outcomes for cancer patients. Overall, we believe combining CAR-T therapy with PD-1 blockade holds promise for the next generation of cancer immunotherapy. | [
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38798125 | 932 | Antibody-drug conjugates, bispecific antibodies and CAR-T cells therapy in multiple myeloma. | Modern immunotherapy approaches are revolutionizing the treatment scenario of relapsed/refractory (RR) multiple myeloma (MM) patients, providing an opportunity to reach deep level of responses and extend survival outcomes.
Antibody-drug conjugates (ADCs) and T-cell redirecting treatments, including bispecific antibodies (BsAbs) and chimeric antigen receptor (CAR) T cells therapy, have been recently introduced in the treatment of RRMM. Some agents have already received regulatory approval, while newer constructs, novel combinations, and applications in earlier lines of therapy are currently being explored. This review discusses the current landscape and possible development of ADCs, BsAbs and CAR-T cells immunotherapies.
ADCs, BsAbs, and CAR-T therapy have demonstrated substantial activity in heavily pretreated, triple-class exposed (TCE) MM patients, and T-cell redirecting treatments represent new standards of care after third (European Medicines Agency, EMA), or fourth (Food and Drug Administration, FDA), line of therapy. All these three immunotherapies carry advantages and disadvantages, with different accessibility and new toxicities that require appropriate management and guidelines. Multiple on-going programs include combinations therapies and applications in earlier lines of treatment, as well as the development of novel agents or construct to enhance potency, reduce toxicity and facilitate administration. Sequencing is a challenge, with few data available and mechanisms of resistance still to be unraveled. | [
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] | 2024-05-27 | 1 | 38798125 | [
"T cells therapy",
"new toxicities",
"combinations therapies",
"treatment",
"new standards",
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"novel combinations",
"T-cell redirecting treatments",
"earlier lines",
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"line",
"CAR-T therapy",
"MM",
"substantial activity",
"regulatory approval",
"appropriate management",
"CAR",
"antigen receptor",
"survival outcomes",
"applications"
] | [
"Multiple myeloma",
"antibody-drug conjugates",
"bispecific antibodies",
"chimeric antigen receptor T cells therapy",
"immunotherapy"
] | 0 | 10.1080/14737140.2024.2344647 | [
"Tacchetti",
"Talarico",
"Barbato",
"Pantani",
"Mancuso",
"Rizzello",
"Zamagni",
"Cavo"
] | [
"IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \"Seràgnoli\", Bologna, Italy.",
"IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \"Seràgnoli\", Bologna, Italy.\nDipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy.",
"IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \"Seràgnoli\", Bologna, Italy.\nDipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy.",
"IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \"Seràgnoli\", Bologna, Italy.",
"IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \"Seràgnoli\", Bologna, Italy.\nDipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy.",
"IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \"Seràgnoli\", Bologna, Italy.\nDipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy.",
"IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \"Seràgnoli\", Bologna, Italy.\nDipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy.",
"IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \"Seràgnoli\", Bologna, Italy.\nDipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy."
] | [
"38798125"
] | [] | 4.868157 | 6.38013 |
38791909 | 933 | Advances in Hodgkin Lymphoma Treatment: From Molecular Biology to Clinical Practice. | Classical Hodgkin Lymphoma (cHL) is a highly curable disease, but around 20% of patients experience progression or relapse after standard frontline chemotherapy regimens. Salvage regimens followed by autologous stem cell transplants represent the historical treatment approach for these cases. In the last decade, with the increasing understanding of cHL biology and tumor microenvironment role in disease course, novel molecules have been introduced in clinical practice, improving outcomes in the relapsed/refractory setting. The anti-CD30 antibody-drug conjugated brentuximab vedotin and PD-1/PD-L1 checkpoint inhibitors represent nowadays curative options for chemorefractory patients, and randomized trials recently demonstrated their efficacy in frontline immune-chemo-combined modalities. Several drugs able to modulate the patients' T-lymphocytes and NK cell activity are under development, as well as many anti-CD30 chimeric antigen receptor T-cell products. Multiple tumor aberrant epigenetic mechanisms are being investigated as targets for antineoplastic compounds such as histone deacetylase inhibitors and hypomethylating agents. Moreover, JAK2 inhibition combined with anti-PD1 blockade revealed a potential complementary therapeutic pathway in cHL. In this review, we will summarize recent findings on cHL biology and novel treatment options clinically available, as well as promising future perspectives in the field. | [
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] | [
"Hematology Division, A.O.U. Città della Salute e della Scienza di Torino, C.so Bramante 88, 10126 Turin, Italy.",
"Hematology Division, A.O.U. Città della Salute e della Scienza di Torino, C.so Bramante 88, 10126 Turin, Italy.",
"Hematology Division, A.O.U. Città della Salute e della Scienza di Torino, C.so Bramante 88, 10126 Turin, Italy.",
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38791898 | 934 | FLT3-Mutated Leukemic Stem Cells: Mechanisms of Resistance and New Therapeutic Targets. | Despite the availability of target drugs in the first and second line, only 30% of FLT3mut AMLs are cured. Among the multiple mechanisms of resistance, those of FLT3mut LSC are the most difficult to eradicate because of their metabolic and genomic characteristics. Reactivation of glycogen synthesis, inhibition of the RAS/MAPK pathway, and degradation of FLT3 may be potential aids to fight the resistance of LSC to FLT3i. LSC is also characterized by the expression of a CD34+/CD25+/CD123+/CD99+ immunophenotype. The receptor and ligand of FLT3, the natural killer group 2 member D ligand (NKGD2L), and CD123 are some of the targets of chimeric antigen receptor T cells (CAR-T), bispecific T-cell engager molecules (BiTEs), CAR-NK and nanoparticles recently designed and reported here. The combination of these new therapeutic options, hopefully in a minimal residual disease (MRD)-driven approach, could provide the future answer to the challenge of treating FLT3mut AML. | [
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38791398 | 935 | Current Advancements in Anti-Cancer Chimeric Antigen Receptor T Cell Immunotherapy and How Nanotechnology May Change the Game. | Chimeric antigen receptor (CAR)-T cell immunotherapy represents a cutting-edge advancement in the landscape of cancer treatment. This innovative therapy has shown exceptional promise in targeting and eradicating malignant tumors, specifically leukemias and lymphomas. However, despite its groundbreaking successes, (CAR)-T cell therapy is not without its challenges. These challenges, particularly pronounced in the treatment of solid tumors, include but are not limited to, the selection of appropriate tumor antigens, managing therapy-related toxicity, overcoming T-cell exhaustion, and addressing the substantial financial costs associated with treatment. Nanomedicine, an interdisciplinary field that merges nanotechnology with medical science, offers novel strategies that could potentially address these limitations. Its application in cancer treatment has already led to significant advancements, including improved specificity in drug targeting, advancements in cancer diagnostics, enhanced imaging techniques, and strategies for long-term cancer prevention. The integration of nanomedicine with (CAR)-T cell therapy could revolutionize the treatment landscape by enhancing the delivery of genes in (CAR)-T cell engineering, reducing systemic toxicity, and alleviating the immunosuppressive effects within the tumor microenvironment. This review aims to explore how far (CAR)-T cell immunotherapy has come alone, and how nanomedicine could strengthen it into the future. Additionally, the review will examine strategies to limit the off-target effects and systemic toxicity associated with (CAR)-T cell therapy, potentially enhancing patient tolerance and treatment outcomes. | [
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10.1016/j.biomaterials.2011.04.023 | [
"Ku",
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] | [
"College of Medicine, California Northstate University, Elk Grove, CA 95757, USA.",
"College of Medicine, California Northstate University, Elk Grove, CA 95757, USA.",
"Section Pathology of the Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747 Jena, Germany.",
"College of Medicine, California Northstate University, Elk Grove, CA 95757, USA.\nCalifornia Pacific Medical Center Research Institute, Sutter Bay Hospitals, San Francisco, CA 94107, USA."
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38789477 | 936 | Ganglioside SSEA-4 in Ewing sarcoma marks a tumor cell population with aggressive features and is a potential cell-surface immune target. | Carbohydrate markers of immature cells during prenatal human development can be aberrantly expressed in cancers and deserve evaluation as immune targets. A candidate target in Ewing sarcoma is the globo-series ganglioside stage-specific embryonic antigen-4 (SSEA-4). We detected SSEA-4 expression on the cell surface of all of 14 EwS cell lines and in 21 of 31 (68%) primary EwS tumor biopsies. Among paired subpopulations of tumor cells with low versus high SSEA-4 expression, SSEA-4 | [
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10.1080/01621459.1958.10501452 | [
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] | [
"Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Albert-Schweitzer Campus 1, 38149, Muenster, Germany.",
"Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Albert-Schweitzer Campus 1, 38149, Muenster, Germany.\nPrincess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands.",
"Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Albert-Schweitzer Campus 1, 38149, Muenster, Germany.",
"Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Albert-Schweitzer Campus 1, 38149, Muenster, Germany.",
"Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Albert-Schweitzer Campus 1, 38149, Muenster, Germany.",
"Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Albert-Schweitzer Campus 1, 38149, Muenster, Germany.",
"Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Albert-Schweitzer Campus 1, 38149, Muenster, Germany.",
"Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Albert-Schweitzer Campus 1, 38149, Muenster, Germany.",
"Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Albert-Schweitzer Campus 1, 38149, Muenster, Germany.",
"Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Albert-Schweitzer Campus 1, 38149, Muenster, Germany.",
"Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Albert-Schweitzer Campus 1, 38149, Muenster, Germany.",
"Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Albert-Schweitzer Campus 1, 38149, Muenster, Germany.",
"Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Albert-Schweitzer Campus 1, 38149, Muenster, Germany.",
"Institute of Biostatistics and Clinical Research, University of Muenster, Schmeddingstr. 56, 48149, Muenster, Germany.",
"Miltenyi Biotec B.V. & Co. KG, Friedrich-Ebert-Straße 68, 51429, Bergisch Gladbach, Germany.",
"Miltenyi Biotec B.V. & Co. KG, Friedrich-Ebert-Straße 68, 51429, Bergisch Gladbach, Germany.",
"Gerhard-Domagk-Institute of Pathology, University of Muenster, Domagkstr. 17, 48149, Muenster, Germany.",
"Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Albert-Schweitzer Campus 1, 38149, Muenster, Germany. [email protected].\nCells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University of Muenster, Roentgenstr. 16, 48149, Muenster, Germany. [email protected].\nPrincess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands. [email protected].",
"Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Albert-Schweitzer Campus 1, 38149, Muenster, Germany.\nPrincess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands."
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38789450 | 937 | Molecular understanding and clinical outcomes of CAR T cell therapy in the treatment of urological tumors. | Chimeric antigen receptor engineered T (CAR T) cell therapy has developed rapidly in recent years, leading to profound developments in oncology, especially for hematologic malignancies. However, given the pressure of immunosuppressive tumor microenvironments, antigen escape, and diverse other factors, its application in solid tumors is less developed. Urinary system tumors are relatively common, accounting for approximately 24% of all new cancers in the United States. CAR T cells have great potential for urinary system tumors. This review summarizes the latest developments of CAR T cell therapy in urinary system tumors, including kidney cancer, bladder cancer, and prostate cancer, and also outlines the various CAR T cell generations and their pathways and targets that have been developed thus far. Finally, the current advantages, problems, and side effects of CAR T cell therapy are discussed in depth, and potential future developments are proposed in view of current shortcomings. | [
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10.1016/j.ccell.2020.07.005 | [
"Zhang",
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"Lu",
"Ding",
"Wang",
"Zhu",
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] | [
"Department of Urology, Shengjing Hospital of China Medical University, Shenyang, 110004, China.",
"Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China.",
"Department of Urology, Shengjing Hospital of China Medical University, Shenyang, 110004, China.",
"Department of Nursing, Shengjing Hospital of China Medical University, Shenyang, 110004, China.",
"Department of Urology, Shengjing Hospital of China Medical University, Shenyang, 110004, China.",
"Department of Family Medicine, Shengjing Hospital of China Medical University, Shenyang, 110004, China. [email protected].",
"Department of Urology, Shengjing Hospital of China Medical University, Shenyang, 110004, China. [email protected].",
"Department of Urology, Shengjing Hospital of China Medical University, Shenyang, 110004, China. [email protected]."
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38788547 | 938 | PD-1-CD28-enhanced receptor and CD19 CAR-modified tumor-infiltrating T lymphocytes produce potential anti-tumor ability in solid tumors. | The limited expansion ability and functional inactivation of T cells within the solid tumor microenvironment are major problems faced during in the application of using tumor-infiltrating lymphocytes (TILs) in vivo. We sought to determine whether TILs carrying a PD-1-CD28-enhanced receptor and CD19 CAR could overcome this limitation and mediate tumor regression. First, anti-tumor effects of PD-1-CD28-enhanced receptor or CD19 CAR modified NY-ESO-1-TCR-T cells to mimic the TILs function (hereafter "PD-1-CD28-TCR-T" or "CD19 CAR-TCR-T" cells, respectively) were tested using the NY-ESO-1 over-expressed tumor cell line in vitro and in a tumor-bearing model. Furthermore, the safety and anti-tumor ability of S-TILs (TILs modified through transduction with a plasmid encoding the PD-1-CD28-T2A-CD19 CAR) were evaluated in vivo. PD-1-CD28-TCR-T cells showed a formidable anti-tumor ability that was not subject to PD-1/PD-L1 signaling in vivo. CD19 CAR-TCR-T cells stimulated with CD19 | [
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] | 2024-05-25 | 1 | 38788547 | [
"CD19 CAR",
"anti-tumor ability",
"T cells",
"anti-tumor effects",
"PD-1",
"CD19",
"TILs",
"a formidable anti-tumor ability",
"CD19 CAR-TCR-T cells",
"functional inactivation",
"major problems",
"CD28-TCR-T cells",
"NY",
"PD-1-CD28-enhanced receptor",
"the solid tumor microenvironment",
"vivo",
"tumor-infiltrating lymphocytes",
"\"CD19 CAR-TCR-T\" cells",
"T2A-CD19",
"a PD-1-CD28-enhanced receptor",
"The limited expansion ability",
"the NY-ESO-1 over-expressed tumor cell line",
"hereafter \"PD-1-CD28-TCR-T",
"the TILs function",
"S-TILs",
"transduction",
"this limitation and mediate tumor regression",
"PD-1/PD-L1",
"a tumor-bearing model",
"-ESO-1-TCR-T"
] | [
"CD28",
"Chimeric antigen receptor (CAR)",
"Programed death 1 receptor (PD-1)",
"Tumor-infiltrating T lymphocytes (TILs)"
] | 0 | 10.1016/j.biopha.2024.116800 | [
"Chen",
"Zhao",
"Mou",
"Zhao",
"Zhang",
"Zhang",
"Huang",
"Liu",
"Wang",
"Zhang",
"Wang",
"Gu",
"Zhang"
] | [
"Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.",
"Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.",
"Chineo Medical Technology Co., Ltd., Beijing 100176, China.",
"Chineo Medical Technology Co., Ltd., Beijing 100176, China.",
"Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.",
"Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.",
"Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.",
"Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.",
"Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.",
"Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.",
"Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.",
"Chineo Medical Technology Co., Ltd., Beijing 100176, China. Electronic address: [email protected].",
"Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou, Henan 450052, China; School of Life Sciences, Zhengzhou University, Zhengzhou, Henan 450052, China; Engineering Key Laboratory for Cell Therapy of Henan Province, Zhengzhou, Henan 450052, China. Electronic address: [email protected]."
] | [
"38788547"
] | [] | 9.59568 | 5.861693 |
38788449 | 939 | CAR-T cell therapy: Efficacy in management of cancers, adverse effects, dose-limiting toxicities and long-term follow up. | Chimeric Antigen Receptor T-cell (CAR-T) therapy has emerged as a groundbreaking and highly promising approach for the management of cancer. This paper reviews the efficacy of CAR-T therapy in the treatment of various hematological malignancies, also, with a mention of its effect on solid tumors, for which they have not received FDA approval yet. Different common and uncommon side effects are also discussed in this paper, with attention to the effect of each drug separately. By reviewing the recommendations of the FDA for CAR-T therapy research, we have extensively discussed dose-limiting toxicities. This further highlights the need for precise dosing strategies, striking a balance between therapeutic benefits and potential risks. Additionally, we reviewed the long-term follow-up of patients receiving CAR-T therapy to gain valuable insights into response durability and late-onset effects. | [
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] | 2024-05-25 | 1 | 38788449 | [
"precise dosing strategies",
"CAR-T therapy research",
"various hematological malignancies",
"therapeutic benefits",
"CAR-T therapy",
"response durability",
"valuable insights",
"solid tumors",
"FDA approval",
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"potential risks",
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"patients",
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"attention",
"cancer",
"dose-limiting toxicities",
"its effect",
"the effect",
"the long-term follow-up",
"a groundbreaking and highly promising approach",
"the FDA",
"This paper",
"this paper",
"a balance",
"the need",
"a mention",
"the treatment",
"the management"
] | [
"CAR-T cell therapy",
"Cytokine release syndrome (CRS)",
"Dose-limiting toxicities",
"ICANS",
"Progression-free survival (PFS)"
] | 0 | 10.1016/j.intimp.2024.112312 | [
"Elmarasi",
"Elkonaissi",
"Elsabagh",
"Elsayed",
"Elsayed",
"Elsayed",
"Elmakaty",
"Yassin"
] | [
"Department of Medical Education, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar.",
"Department of Hematology, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates.",
"Department of Medical Education, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar.",
"College of Medicine, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar.",
"Department of Medical Education, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar.",
"Department of Medical Education, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar.",
"Department of Medical Education, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar. Electronic address: [email protected].",
"College of Medicine, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar; Hematology Section, Medical Oncology, National Center for Cancer Care and Research (NCCCR), Hamad Medical Corporation (HMC), P.O. Box 3050, Doha, Qatar. Electronic address: [email protected]."
] | [
"38788449"
] | [] | 7.569424 | 3.961961 |
38786075 | 940 | Multiple Myeloma: The Role of Autologous Stem Cell Transplantation in the Era of Immunotherapy. | Upfront high-dose therapy with melphalan (HDM) followed by autologous stem cell transplantation (ASCT) has established itself as a core treatment for newly diagnosed multiple myeloma (NDMM) patients in the past 30 years. Induction therapy, HDM-ASCT, and subsequent consolidation and maintenance therapy comprise the current fundamental framework for MM treatment. The introduction of anti-CD38 monoclonal antibodies such as daratumumab and isatuximab has changed the treatment paradigm for transplant-eligible NDMM patients in that quadruplets have become the new standard induction therapy. The treatment landscape of MM is undergoing a transformative shift with the introduction of potent new immunotherapies, such as chimeric antigen receptor (CAR)-T cells and bispecific antibodies (BsAbs), which are currently used in the relapsed/refractory setting (RRMM) and are already being tested in the NDMM. This review will focus on the incorporation of immunotherapy in the treatment scenario of NDMM patients eligible for ASCT. | [
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38783803 | 941 | [Advances of CAR-T cell therapy in treating colorectal cancer]. | Globally, colorectal cancer (CRC) ranks as the third most common cancer and the second leading cause of cancer-related fatalities. According to the World Health Organization, there are over 1.9 million annual cases of CRC diagnosed worldwide, resulting in more than 900 000 deaths. In recent years, chimeric antigen receptor T (CAR-T) cell therapy has shown clinical success in treating certain hematological malignancies and is now being explored for its potential in targeting solid tumors like CRC. Currently, CAR-T cell therapies targeting carcinoembryonic antigen (CEA), natural killer group 2, member D ligand (NKG2DL), and other markers have achieved remarkable results in clinical trials, albeit encountering significant challenges. This review summarizes the promising targets of CAR-T cell therapy for CRC and highlights progress made in clinical trials and preclinical studies. Additionally, the review discusses the challenges faced by CAR-T cell therapy in CRC treatment, including a shortage of tumor-specific antigens, cytokine release syndrome, adverse tumor microenvironment, and limited infiltration of CAR-T cells. In summary, this review provides an overview of the latest research progress and challenges in CAR-T cell therapy for CRC, aiming to contribute fresh insights for the clinical treatment of this disease. | [
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"CRC treatment",
"clinical trials",
"CRC",
"clinical success",
"CAR-T cell therapies",
"CAR-T cell therapy",
"carcinoembryonic antigen",
"adverse tumor microenvironment",
"solid tumors",
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"natural killer group",
"significant challenges",
"certain hematological malignancies",
"colorectal cancer",
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"other markers",
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"CRC and highlights progress",
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] | [
"chimeric antigen receptor T (CAR-T) cell therapy",
"clinical trials",
"colorectal cancer",
"targeted therapy"
] | 0 | 10.13345/j.cjb.230741 | [
"Chao",
"Liu",
"Liu"
] | [
"College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430065, Hubei, China.",
"College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430065, Hubei, China.",
"College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430065, Hubei, China."
] | [
"38783803"
] | [] | 10.819197 | 5.199435 |
38783801 | 942 | [Application of mRNA nano-delivery system in CAR-T tumor immunotherapy]. | Chimeric antigen receptor T cells (CAR-T) immunotherapy, which activates immunity specific to the system in order to achieve antitumor effects, has experienced exciting progress in recent years. mRNA nano-delivery systems, which encapsulate tumor immunotherapy-related antigen mRNA with nanoparticles, have shown great potential in CAR-T tumor immunotherapy. On one hand, these systems can directly target T cells to generate CAR-T cells that directly act upon the corresponding tumor cells. On the other hand, they can be delivered to antigen-presenting cells through targeting, thereby enhancing the function of CAR-T cells and further inducing specific immune responses against tumor cells. This review summarizes the synthesis of mRNA nano-delivery systems and their application in CAR-T tumor immunotherapy. | [
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"Chimeric antigen receptor T cells",
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] | [
"chimeric antigen receptor T cells (CAR-T)",
"in vitro-transcribe mRNA",
"nano-delivery system",
"tumor immunotherapy"
] | 0 | 10.13345/j.cjb.230541 | [
"Zeng",
"Wei",
"Sun",
"Xu"
] | [
"College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430065, Hubei, China.",
"College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430065, Hubei, China.",
"College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430065, Hubei, China.",
"College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430065, Hubei, China."
] | [
"38783801"
] | [] | 9.960308 | 3.479768 |
38783333 | 943 | BCMA/CD47-directed universal CAR-T cells exhibit excellent antitumor activity in multiple myeloma. | BCMA-directed autologous chimeric antigen receptor T (CAR-T) cells have shown excellent clinical efficacy in relapsed or refractory multiple myeloma (RRMM), however, the current preparation process for autologous CAR-T cells is complicated and costly. Moreover, the upregulation of CD47 expression has been observed in multiple myeloma, and anti-CD47 antibodies have shown remarkable results in clinical trials. Therefore, we focus on the development of BCMA/CD47-directed universal CAR-T (UCAR-T) cells to improve these limitations.
In this study, we employed phage display technology to screen nanobodies against BCMA and CD47 protein, and determined the characterization of nanobodies. Furthermore, we simultaneously disrupted the endogenous TRAC and B2M genes of T cells using CRISPR/Cas9 system to generate TCR and HLA double knock-out T cells, and developed BCMA/CD47-directed UCAR-T cells and detected the antitumor activity in vitro and in vivo.
We obtained fourteen and one specific nanobodies against BCMA and CD47 protein from the immunized VHH library, respectively. BCMA/CD47-directed UCAR-T cells exhibited superior CAR expression (89.13-98.03%), and effectively killing primary human MM cells and MM cell lines. BCMA/CD47-directed UCAR-T cells demonstrated excellent antitumor activity against MM and prolonged the survival of tumor-engrafted NCG mice in vivo.
This work demonstrated that BCMA/CD47-directed UCAR-T cells exhibited potent antitumor activity against MM in vitro and in vivo, which provides a potential strategy for the development of a novel "off-the-shelf" cellular immunotherapies for the treatment of multiple myeloma. | [
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"tumor-engrafted NCG mice"
] | [
"Immunotherapy",
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10.1038/s41551-021-00730-z | [
"Lu",
"Li",
"Wu",
"Zhu",
"Zhang",
"Yang",
"Tong"
] | [
"Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.",
"Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.",
"Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.",
"Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.",
"Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.",
"College of Veterinary Medicine, Shaanxi Center of Stem Cells Engineering and Technology, Northwest A&F University, Yangling, 712100, China.",
"Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. [email protected].\nFrontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212, China. [email protected]."
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38783148 | 944 | Mapping variant effects on anti-tumor hallmarks of primary human T cells with base-editing screens. | Single-nucleotide variants (SNVs) in key T cell genes can drive clinical pathologies and could be repurposed to improve cellular cancer immunotherapies. Here, we perform massively parallel base-editing screens to generate thousands of variants at gene loci annotated with known or potential clinical relevance. We discover a broad landscape of putative gain-of-function (GOF) and loss-of-function (LOF) mutations, including in PIK3CD and the gene encoding its regulatory subunit, PIK3R1, LCK, SOS1, AKT1 and RHOA. Base editing of PIK3CD and PIK3R1 variants in T cells with an engineered T cell receptor specific to a melanoma epitope or in different generations of CD19 chimeric antigen receptor (CAR) T cells demonstrates that discovered GOF variants, but not LOF or silent mutation controls, enhanced signaling, cytokine production and lysis of cognate melanoma and leukemia cell models, respectively. Additionally, we show that generations of CD19 CAR T cells engineered with PIK3CD GOF mutations demonstrate enhanced antigen-specific signaling, cytokine production and leukemia cell killing, including when benchmarked against other recent strategies. | [
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] | 2024-05-24 | 62 | 38783148 | [
"key T cell genes",
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"T cells",
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"leukemia cell models",
"GOF variants",
"gene loci",
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"enhanced signaling, cytokine production",
"function",
"LCK",
"PIK3R1",
"Single-nucleotide variants",
"enhanced antigen-specific signaling",
"known or potential clinical relevance",
"SOS1"
] | [] | 0 | 10.1038/s41587-024-02235-x
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10.1038/s41586-018-0326-5 | [
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"Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.\nDepartment of Medicine, Division of Hematology and Oncology, Columbia University Irving Medical Center, New York, NY, USA.\nColumbia Center for Translational Immunology, New York, NY, USA.\nHerbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.",
"Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.\nDepartment of Medicine, Division of Hematology and Oncology, Columbia University Irving Medical Center, New York, NY, USA.\nColumbia Center for Translational Immunology, New York, NY, USA.\nHerbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.",
"Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.",
"Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.",
"Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA.",
"Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.\nDepartment of Medicine, Division of Hematology and Oncology, Columbia University Irving Medical Center, New York, NY, USA.\nColumbia Center for Translational Immunology, New York, NY, USA.\nHerbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.",
"Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.\nDepartment of Genetics and Development, Columbia University Medical Center, New York, NY, USA.",
"Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.\nDepartment of Medicine, Division of Hematology and Oncology, Columbia University Irving Medical Center, New York, NY, USA.\nColumbia Center for Translational Immunology, New York, NY, USA.\nHerbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.",
"Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.\nDepartment of Medicine, Division of Hematology and Oncology, Columbia University Irving Medical Center, New York, NY, USA.\nColumbia Center for Translational Immunology, New York, NY, USA.\nHerbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.",
"Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.\nDepartment of Medicine, Division of Hematology and Oncology, Columbia University Irving Medical Center, New York, NY, USA.\nColumbia Center for Translational Immunology, New York, NY, USA.\nHerbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.",
"Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.\nDepartment of Medicine, Division of Hematology and Oncology, Columbia University Irving Medical Center, New York, NY, USA.\nColumbia Center for Translational Immunology, New York, NY, USA.\nHerbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.",
"Department of Medicine, Division of Hematology and Oncology, Columbia University Irving Medical Center, New York, NY, USA.\nHerbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.",
"Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA.",
"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA.",
"Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.\nDepartment of Genetics and Development, Columbia University Medical Center, New York, NY, USA.",
"Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.\nDepartment of Medicine, Division of Hematology and Oncology, Columbia University Irving Medical Center, New York, NY, USA.\nColumbia Center for Translational Immunology, New York, NY, USA.\nHerbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.",
"Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA. [email protected].\nDepartment of Medicine, Division of Hematology and Oncology, Columbia University Irving Medical Center, New York, NY, USA. [email protected].\nColumbia Center for Translational Immunology, New York, NY, USA. [email protected].\nHerbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA. [email protected].\nDepartment of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA. [email protected]."
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38781564 | 945 | Phase 1 study of CAR-37 T cells in patients with relapsed or refractory CD37+ lymphoid malignancies. | We report a first-in-human clinical trial using chimeric antigen receptor (CAR) T cells targeting CD37, an antigen highly expressed in B- and T-cell malignancies. Five patients with relapsed or refractory CD37+ lymphoid malignancies were enrolled and infused with autologous CAR-37 T cells. CAR-37 T cells expanded in the peripheral blood of all patients and, at peak, comprised >94% of the total lymphocytes in 4 of 5 patients. Tumor responses were observed in 4 of 5 patients with 3 complete responses, 1 mixed response, and 1 patient whose disease progressed rapidly and with relative loss of CD37 expression. Three patients experienced prolonged and severe pancytopenia, and in 2 of these patients, efforts to ablate CAR-37 T cells, which were engineered to coexpress truncated epidermal growth factor receptor, with cetuximab were unsuccessful. Hematopoiesis was restored in these 2 patients after allogeneic hematopoietic stem cell transplantation. No other severe, nonhematopoietic toxicities occurred. We investigated the mechanisms of profound pancytopenia and did not observe activation of CAR-37 T cells in response to hematopoietic stem cells in vitro or hematotoxicity in humanized models. Patients with pancytopenia had sustained high levels of interleukin-18 (IL-18) with low levels of IL-18 binding protein in their peripheral blood. IL-18 levels were significantly higher in CAR-37-treated patients than in both cytopenic and noncytopenic cohorts of CAR-19-treated patients. In conclusion, CAR-37 T cells exhibited antitumor activity, with significant CAR expansion and cytokine production. CAR-37 T cells may be an effective therapy in hematologic malignancies as a bridge to hematopoietic stem cell transplant. This trial was registered at www.ClinicalTrials.gov as #NCT04136275. | [
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] | 2024-05-23 | 1 | 38781564 | [
"CAR-37 T cells",
"autologous CAR-37 T cells",
"hematopoietic stem cells",
"hematopoietic stem cell transplant",
"allogeneic hematopoietic stem cell transplantation",
"Patients",
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"response",
"B- and T-cell malignancies",
"relative loss",
"cytokine production",
"1 patient",
"Five patients",
"Three patients",
"all patients"
] | [] | 0 | 10.1182/blood.2024024104 | [
"Frigault",
"Graham",
"Berger",
"Ritchey",
"Horick",
"El-Jawahri",
"Scarfò",
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"DiPersio",
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] | [
"Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA.\nHematopoietic Cell Transplant and Cellular Therapy Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA.\nDepartment of Pathology and Department of Medicine, Harvard Medical School, Boston, MA.",
"Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA.\nDepartment of Pathology and Department of Medicine, Harvard Medical School, Boston, MA.",
"Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA.",
"Department of Medicine, Washington University School of Medicine, St. Louis, MO.",
"Department of Biostatistics, Massachusetts General Hospital and Harvard Medical School, Boston, MA.",
"Hematopoietic Cell Transplant and Cellular Therapy Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA.\nDepartment of Pathology and Department of Medicine, Harvard Medical School, Boston, MA.",
"Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA.\nDepartment of Pathology and Department of Medicine, Harvard Medical School, Boston, MA.",
"Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA.\nDepartment of Pathology and Department of Medicine, Harvard Medical School, Boston, MA.",
"Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA.",
"Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA.\nDepartment of Pathology and Department of Medicine, Harvard Medical School, Boston, MA.",
"Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA.",
"Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA.",
"Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA.",
"Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA.",
"Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA.",
"Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA.\nHematopoietic Cell Transplant and Cellular Therapy Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA.\nDepartment of Pathology and Department of Medicine, Harvard Medical School, Boston, MA.",
"Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA.",
"Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA.",
"Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA.",
"Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA.",
"Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA.",
"Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA.",
"Department of Pathology and Department of Medicine, Harvard Medical School, Boston, MA.\nConnell and O'Reilly Families Cell Manipulation Core Facility, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.",
"Connell and O'Reilly Families Cell Manipulation Core Facility, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.",
"Department of Pathology and Department of Medicine, Harvard Medical School, Boston, MA.\nConnell and O'Reilly Families Cell Manipulation Core Facility, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.",
"TransLab, Boston Children's Hospital, Boston, MA.",
"Department of Pathology and Department of Medicine, Harvard Medical School, Boston, MA.\nDepartment of Pathology, Massachusetts General Hospital, Boston, MA.",
"Department of Medicine, Washington University School of Medicine, St. Louis, MO.",
"Department of Pathology and Department of Medicine, Harvard Medical School, Boston, MA.\nDepartment of Pathology, Massachusetts General Hospital, Boston, MA.",
"Hematopoietic Cell Transplant and Cellular Therapy Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA.\nDepartment of Pathology and Department of Medicine, Harvard Medical School, Boston, MA.",
"Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA.\nDepartment of Pathology and Department of Medicine, Harvard Medical School, Boston, MA.\nDepartment of Pathology, Massachusetts General Hospital, Boston, MA.",
"Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA.\nHematopoietic Cell Transplant and Cellular Therapy Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA.\nDepartment of Pathology and Department of Medicine, Harvard Medical School, Boston, MA.\nCancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA."
] | [
"38781564"
] | [] | 7.030402 | 5.604402 |
38781557 | 946 | Immunotherapy in Sarcoma: Current Data and Promising Strategies. | Traditionally sarcomas have been considered immunologically quiet tumours, with low tumour mutational burden (TMB) and an immunosuppressive tumour microenvironment (TME), consisting of decreased T-cell infiltration and elevated levels of H1F1α, macrophages and neutrophils. | [
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] | 2024-05-23 | 1 | 38781557 | [
"low tumour mutational burden",
"elevated levels",
"an immunosuppressive tumour microenvironment",
"decreased T-cell infiltration",
"TME",
"H1F1α",
"TMB",
"macrophages",
"immunologically quiet tumours",
"neutrophils",
"Traditionally sarcomas"
] | [] | 0 | 10.1200/EDBK_432234 | [
"Wood",
"Meyer",
"Petitprez",
"D'Angelo"
] | [
"University College Hospital of London, London, United Kingdom.",
"Johns Hopkins, Baltimore, MD.",
"The University of Edinburgh, Edinburgh, Scotland.",
"Memorial Sloan Kettering Cancer Center, New York, NY."
] | [
"38781557"
] | [] | 10.523798 | 6.12022 |
38781075 | 947 | Protocol for preclinical evaluation of locoregionally delivered CAR T cells in patient-derived xenograft models of brain tumors. | Here, we present a protocol for preclinical evaluation of locoregionally delivered CAR T cells in patient-derived xenograft models of primary, metastatic, and recurrent brain tumors. We provide instructions for isolating peripheral blood mononuclear cells (PBMCs), producing CAR T cells in conjunction with locoregional delivery, and preclinical trial design and analysis involving CAR T cells. Additionally, we describe comprehensive preclinical readouts and guidelines for critical endpoint sample collections. In line with clinical trial procedures, our protocol broadens available treatment modalities for direct clinical translation. For complete details on the use and execution of this protocol, please refer to Donovan et al. | [
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10.1038/s41591-020-0827-2
10.1016/j.xcrm.2021.100457
10.1016/j.immuni.2016.07.011
10.1126/sciimmunol.ade3369 | [
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"UCL Great Ormond Street Institute of Child Health, London WC1N 1DZ, England.",
"UCL Great Ormond Street Institute of Child Health, London WC1N 1DZ, England.",
"UCL Great Ormond Street Institute of Child Health, London WC1N 1DZ, England.",
"UCL Great Ormond Street Institute of Child Health, London WC1N 1DZ, England.",
"UCL Great Ormond Street Institute of Child Health, London WC1N 1DZ, England.",
"Department of Paediatrics, Section of Haematology-Oncology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA.",
"Department of Paediatrics, Section of Haematology-Oncology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA.",
"UCL Great Ormond Street Institute of Child Health, London WC1N 1DZ, England. Electronic address: [email protected]."
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38780683 | 948 | Talicabtagene Autoleucel: First Approval. | Talicabtagene autoleucel (NexCAR19™) is a chimeric antigen receptor (CAR) T-cell therapy being developed by the Indian Institute of Technology, Bombay (IIT-B) and Immunoadoptive Cell Therapy (ImmunoACT) for the treatment of relapsed/refractory B-cell malignancies. Talicabtagene autoleucel contains autologous T cells from the patient, which have been modified to express a humanized anti-CD19 CAR that targets B cells. A single intravenous dose of talicabtagene autoleucel was associated with high response rates in pooled results from a phase I and phase II trial in patients with relapsed/refractory B-cell malignancies. Talicabtagene autoleucel was approved in India for the treatment of relapsed/refractory B-cell lymphomas and relapsed/refractory B-cell acute lymphoblastic leukaemia on 13 October 2023. This article summarizes the milestones in the development of talicabtagene autoleucel leading to this first approval for relapsed/refractory B-cell lymphomas and relapsed/refractory B-cell acute lymphoblastic leukaemia. | [
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"autologous T cells",
"B cells",
"relapsed/refractory B-cell acute lymphoblastic leukaemia",
"Talicabtagene",
"talicabtagene",
"high response rates",
"relapsed/refractory B-cell lymphomas",
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"the Indian Institute",
"this first approval",
"the Indian Institute of Technology",
"the patient",
"the treatment"
] | [] | 0 | 10.1007/s40291-024-00719-9
10.1016/j.currproblcancer.2021.100826
10.1016/j.tracli.2023.05.001
10.1158/1535-7163.MCT-20-0476
10.1038/d41586-024-00809-y
10.1038/s41587-023-02049-3
10.1182/blood-2023-180867
10.1182/blood-2023-177594
10.1182/blood-2022-166082 | [
"Nie"
] | [
"Springer Nature, Mairangi Bay, Private Bag 65901, Auckland, 0754, New Zealand. [email protected]."
] | [
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38779743 | 949 | Simultaneous targeting of B-cell malignancies and human immunodeficiency virus with bispecific chimeric antigen receptor T cells. | null | [
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] | 2024-05-23 | 15 | 38779743 | [] | [] | 0 | 10.3324/haematol.2024.285321 | [
"Urak",
"Pahlavanneshan",
"Gittins",
"Nakamura",
"Zaia",
"Baird",
"Clark",
"Forman",
"Wang"
] | [
"Cellular Immunotherapy Center, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA, 91010.",
"Cellular Immunotherapy Center, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA, 91010.",
"Cellular Immunotherapy Center, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA, 91010.",
"Cellular Immunotherapy Center, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA, 91010.",
"Center for Gene Therapy, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, 91010.",
"Cellular Immunotherapy Center, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA, 91010.",
"Department of Clinical and Translational Project Development, City of Hope, Duarte, CA, 91010.",
"Cellular Immunotherapy Center, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA, 91010.",
"Cellular Immunotherapy Center, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA, 91010. [email protected]."
] | [
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"33570626",
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] | [] | 32.88493 | 7.42118 |
38779672 | 950 | Newer generations of multi-target CAR and STAb-T immunotherapeutics: NEXT CART Consortium as a cooperative effort to overcome current limitations. | Adoptive T cellular immunotherapies have emerged as relevant approaches for treating cancer patients who have relapsed or become refractory (R/R) to traditional cancer treatments. Chimeric antigen receptor (CAR) T-cell therapy has improved survival in various hematological malignancies. However, significant limitations still impede the widespread adoption of these therapies in most cancers. To advance in this field, six research groups have created the "NEXT Generation CART MAD Consortium" (NEXT CART) in Madrid's Community, which aims to develop novel cell-based immunotherapies for R/R and poor prognosis cancers. At NEXT CART, various basic and translational research groups and hospitals in Madrid concur to share and synergize their basic expertise in immunotherapy, gene therapy, and immunological synapse, and clinical expertise in pediatric and adult oncology. NEXT CART goal is to develop new cell engineering approaches and treatments for R/R adult and pediatric neoplasms to evaluate in multicenter clinical trials. Here, we discuss the current limitations of T cell-based therapies and introduce our perspective on future developments. Advancement opportunities include developing allogeneic products, optimizing CAR signaling domains, combining cellular immunotherapies, multi-targeting strategies, and improving tumor-infiltrating lymphocytes (TILs)/T cell receptor (TCR) therapy. Furthermore, basic studies aim to identify novel tumor targets, tumor molecules in the tumor microenvironment that impact CAR efficacy, and strategies to enhance the efficiency of the immunological synapse between immune and tumor cells. Our perspective of current cellular immunotherapy underscores the potential of these treatments while acknowledging the existing hurdles that demand innovative solutions to develop their potential for cancer treatment fully. | [
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10.1016/j.eclinm.2021.101086 | [
"Martín-Antonio",
"Blanco",
"González-Murillo",
"Hidalgo",
"Minguillón",
"Pérez-Chacón",
null
] | [
"Department of Experimental Hematology, Instituto de Investigación Sanitaria-Fundación Jiménez Diaz (IIS-FJD), Madrid, Spain.",
"Cancer Immunotherapy Unit (UNICA), Department of Immunology, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain.",
"Department of Pediatric Hematology and Oncology, Advanced Therapies Unit, Fundación Investigación Biomédica Hospital Infantil Universitario Niño Jesús, Madrid, Spain.",
"Cellular Biotechnology Unit, Instituto de Salud Carlos III (ISCIII), Madrid, Spain.",
"La Paz Hospital Institute for Health Research (IdiPAZ), Hospital Universitario La Paz. Universidad Autónoma de Madrid (UAM), Madrid, Spain.",
"Immunity, Immunopathology and Emergent Therapies Group. Instituto de Investigaciones Biomedicas Sols-Morreale. CSIC-UAM, Madrid, Spain.",
null
] | [
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] | [] | 9.335545 | 3.861078 |
38777913 | 951 | Current progress of CAR-T-cell therapy for patients with multiple myeloma. | Currently available chimeric antigen receptor (CAR)-engineered T-cell therapies targeting B-cell maturation antigen (BCMA), namely, idecabtagene vicleucel and ciltacabtagene autoleucel, have shown marked efficacy against relapsed and refractory multiple myeloma. However, further improvement in CAR-T-cell function is warranted as most patients treated with these products eventually relapse due to various mechanisms such as antigen loss and T-cell dysfunction or disappearance. Strategies for improving CAR-T-cell function include targeting of dual antigens, enhancing cell longevity through genetic modification, and eliminating the immunosuppressive tumor microenvironment. Serious side effects can also occur after CAR-T-cell infusions. Although understanding of the molecular pathogenesis of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome is growing, the unique movement disorder caused by BCMA-targeted therapy is less understood, and its molecular mechanisms must be further elucidated to establish better management strategies. In this article, we will review the current status of BCMA-targeting CAR-T-cell therapy. We will also highlight progress in the development of CAR-T cells targeting other antigens, as well as universal allogeneic CAR-T cells and bispecific antibodies. | [
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] | [
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10.1158/2643-3230.Bcd-23-0176 | [
"Nakashima",
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] | [
"Division of Tumor Immunology, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.\nDepartment of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.",
"Division of Tumor Immunology, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. [email protected]."
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38777680 | 952 | Intracranial CAR-T cell delivery in glioblastoma patients. | Chimeric antigen receptor (CAR)-T cell therapy is emerging as a promising approach for improving outcomes in high-grade glioma. Here, we highlight three recent studies that reported safety and feasibility of intracranial CAR-T cell administration in patients with glioblastoma (GBM) as well as preliminary evidence of potential responses, supporting further investigations of this approach. | [
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] | 2024-05-23 | 1 | 38777680 | [
"CAR)-T cell therapy",
"potential responses",
"preliminary evidence",
"Chimeric antigen receptor",
"intracranial CAR-T cell administration",
"further investigations",
"outcomes",
"safety",
"CAR)-T",
"feasibility",
"GBM",
"glioblastoma",
"patients",
"a promising approach",
"high-grade glioma",
"three recent studies",
"this approach",
"that",
"three",
"we"
] | [
"CAR-T cells",
"clinical trial",
"glioblastoma",
"immunotherapy"
] | 0 | 10.1016/j.trecan.2024.05.002 | [
"Vaughn-Beaucaire",
"Choi",
"Liang",
"Lawler"
] | [
"Department of Pathology and Laboratory Medicine, Legoretta Cancer Center, Brown University, Providence, RI 02903, USA.",
"Division of Hematology/Oncology, Lifespan Cancer Institute, Legoretta Cancer Center, Brown University, Providence, RI 02903, USA.",
"Division of Hematology/Oncology, Lifespan Cancer Institute, Legoretta Cancer Center, Brown University, Providence, RI 02903, USA.",
"Department of Pathology and Laboratory Medicine, Legoretta Cancer Center, Brown University, Providence, RI 02903, USA. Electronic address: [email protected]."
] | [
"38777680"
] | [] | 10.011868 | 7.351633 |
38776397 | 953 | Absolute lymphocyte count after BCMA CAR-T therapy is a predictor of response and outcomes in relapsed multiple myeloma. | B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor T cells (CAR-Ts) used in multiple myeloma (MM) are rapidly becoming a mainstay in the treatment of relapsed/refractory (R/R) disease, and CAR-T expansion after infusion has been shown to inform depth and duration of response (DoR), but measuring this process remains investigational. This multicenter study describes the kinetics and prognostic impact of absolute lymphocyte count (ALC) in the first 15 days after CAR-T infusion in 156 patients with relapsed MM treated with the BCMA-targeting agents ciltacabtagene autoleucel and idecabtagene vicleucel. Patients with higher maximum ALC (ALCmax) had better depth of response, progression-free survival (PFS), and DoR. Patients with ALCmax >1.0 × 103/μL had a superior PFS (30.5 months vs 6 months; P < .001) compared with those with ≤1.0 × 103/μL, whereas patients with ALCmax ≤0.5 × 103/μL represent a high-risk group with early disease progression and short PFS (hazard ratio, 3.4; 95% confidence interval, 2-5.8; P < .001). In multivariate analysis, ALCmax >1.0 × 103/μL and nonparaskeletal extramedullary disease were the only independent predictors of PFS and DoR after accounting for international staging systemic staging, age, CAR-T product, high-risk cytogenetics, and the number of previous lines. Moreover, our flow cytometry data suggest that ALC is a surrogate for BCMA CAR-T expansion and can be used as an accessible prognostic marker. We report, to our knowledge, for the first time the association of ALC after BCMA CAR-T infusion with clinical outcomes and its utility in predicting response in patients with R/R MM. | [
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] | 2024-05-22 | 19 | 38776397 | [
"higher maximum ALC",
"early disease progression",
"relapsed MM",
"ALC",
"nonparaskeletal extramedullary disease",
"short PFS",
"international staging systemic staging",
"ALCmax",
"prognostic impact",
"BCMA",
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"Patients",
"patients",
"×",
"BCMA CAR-T infusion",
"response",
"absolute lymphocyte count",
"BCMA CAR-T expansion",
"infusion",
"better depth",
"MM",
"(BCMA)-targeting chimeric antigen receptor T cells",
"DoR",
"hazard ratio",
"CAR-T infusion",
"R/R MM",
"multiple myeloma",
"depth",
"CAR-T expansion",
"clinical outcomes"
] | [] | 0 | 10.1182/bloodadvances.2023012470 | [
"Mejia Saldarriaga",
"Pan",
"Unkenholz",
"Mouhieddine",
"Velez-Hernandez",
"Engles",
"Fein",
"Monge",
"Rosenbaum",
"Pearse",
"Jayabalan",
"Gordillo",
"Chan",
"Yamshon",
"Thibaud",
"Mapara",
"Inghirami",
"Lentzsch",
"Reshef",
"Rossi",
"Parekh",
"Jagannath",
"Richard",
"Niesvizky",
"Bustoros"
] | [
"Division of Hematology & Medical Oncology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY.",
"Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.",
"Division of Hematology & Medical Oncology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY.",
"Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.",
"Division of Hematology & Medical Oncology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY.\nDepartment of Internal Medicine, Universidad de Antioquia, Medellin, Colombia.",
"Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.",
"Division of Hematology & Medical Oncology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY.",
"Division of Hematology & Medical Oncology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY.",
"Division of Hematology & Medical Oncology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY.",
"Division of Hematology & Medical Oncology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY.",
"Department of Internal Medicine, Universidad de Antioquia, Medellin, Colombia.",
"Division of Hematology & Oncology, Columbia University Irving Cancer Center, New York, NY.",
"Division of Hematology & Oncology, Columbia University Irving Cancer Center, New York, NY.",
"Division of Hematology & Medical Oncology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY.",
"Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.",
"Division of Hematology & Oncology, Columbia University Irving Cancer Center, New York, NY.",
"Department of Pathology, Weill Cornell Medicine, New York, NY.",
"Division of Hematology & Oncology, Columbia University Irving Cancer Center, New York, NY.",
"Division of Hematology & Oncology, Columbia University Irving Cancer Center, New York, NY.",
"Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.",
"Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.",
"Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.",
"Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.",
"Division of Hematology & Medical Oncology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY.",
"Division of Hematology & Medical Oncology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY."
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38774284 | 954 | Current immunotherapeutic approaches to diffuse intrinsic pontine glioma. | Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumour that occurs in the pons of the brainstem and accounts for over 80% of all brainstem gliomas. The median age at diagnosis is 6-7 years old, with less than 10% overall survival 2 years after diagnosis and less than 1% after 5 years. DIPGs are surgically inaccessible, and radiation therapy provides only transient benefit, with death ensuing from relentless local tumour infiltration. DIPGs are now the leading cause of brain tumour deaths in children, with a societal cancer burden in years of life lost (YLL) of more than 67 per individual, | [
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] | [
"blood-brain barrier (BBB)",
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10.3389/fimmu.2023.1145706 | [
"Lin",
"Smith",
"Rutka"
] | [
"Cell Biology Research Program, The Hospital for Sick Children, Toronto, ON, Canada.\nArthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.\nDepartment of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.",
"Cell Biology Research Program, The Hospital for Sick Children, Toronto, ON, Canada.\nArthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.",
"Cell Biology Research Program, The Hospital for Sick Children, Toronto, ON, Canada.\nArthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.\nDepartment of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.\nDivision of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada.\nDivision of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada."
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38773607 | 955 | Unraveling resistance mechanisms in anti-CD19 chimeric antigen receptor-T therapy for B-ALL: a novel in vitro model and insights into target antigen dynamics. | Cellular immunotherapy, represented by the chimeric antigen receptor T cell (CAR-T), has exhibited high response rates, durable remission, and safety in vitro and in clinical trials. Unfortunately, anti-CD19 CAR-T (CART-19) treatment alone is prone to relapse and has a particularly poor prognosis in relapsed/refractory (r/r) B-ALL patients. To date, addressing or reducing relapse remains one of the research priorities to achieve broad clinical application.
We manufactured second generation CART-19 cells and validated their efficacy and safety in vitro and in vivo. Through co-culture of Nalm-6 cells with short-term cultured CART-19 cells, CD19-negative Nalm-6 cells were detected by flow cytometry, and further investigation of the relapsed cells and their resistance mechanisms was evaluated in vitro.
In this study, we demonstrated that CART-19 cells had enhanced and specific antileukemic activities, and the survival of B-ALL mouse models after CART-19 treatment was significantly prolonged. We then shortened the culture time and applied the serum-free culture to expand CAR-T cells, followed by co-culturing CART-19 cells with Nalm-6 cells. Surprisingly, we observed the proliferation of CD19-negative Nalm-6 cells around 28 days. Identification of potential resistance mechanisms showed that the relapsed cells express truncated CD19 proteins with decreased levels and, more importantly, CAR expression was detected on the relapsed cell surface, which may ultimately keep them antigen-negative. Furthermore, it was validated that CART-22 and tandem CART-22/19 cells could effectively kill the relapsed cells, but neither could completely eradicate them.
We successfully generated CART-19 cells and obtained a CD19-negative refractory relapsed B-ALL cell line, providing new insights into the underlying mechanisms of resistance and a new in vitro model for the treatment of r/r B-ALL patients with low antigen density. | [
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10.1038/s41591-018-0201-9 | [
"Li",
"Wang",
"Liu",
"Li",
"Zhang",
"Chen",
"Zhao",
"Li",
"Wang",
"Tang"
] | [
"Department/Center of Hematology-oncology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.\nPediatric Leukemia Diagnostic and Therapeutic Technology Research Center of Zhejiang Province, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.",
"Department/Center of Hematology-oncology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.\nPediatric Leukemia Diagnostic and Therapeutic Technology Research Center of Zhejiang Province, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.",
"Department/Center of Hematology-oncology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.\nPediatric Leukemia Diagnostic and Therapeutic Technology Research Center of Zhejiang Province, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.",
"Department of Pediatrics, The First People's Hospital of Wenling, Wenling, Zhejiang, China.",
"Department/Center of Hematology-oncology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.\nPediatric Leukemia Diagnostic and Therapeutic Technology Research Center of Zhejiang Province, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.",
"Department/Center of Hematology-oncology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.\nPediatric Leukemia Diagnostic and Therapeutic Technology Research Center of Zhejiang Province, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.",
"Department/Center of Hematology-oncology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.\nPediatric Leukemia Diagnostic and Therapeutic Technology Research Center of Zhejiang Province, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.",
"Department/Center of Hematology-oncology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.\nPediatric Leukemia Diagnostic and Therapeutic Technology Research Center of Zhejiang Province, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.",
"Department/Center of Hematology-oncology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.\nPediatric Leukemia Diagnostic and Therapeutic Technology Research Center of Zhejiang Province, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.",
"Department/Center of Hematology-oncology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China. [email protected].\nPediatric Leukemia Diagnostic and Therapeutic Technology Research Center of Zhejiang Province, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China. [email protected]."
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38772686 | 956 | Developing a membrane-proximal CD33-targeting CAR T cell. | CD33 is a tractable target in acute myeloid leukemia (AML) for chimeric antigen receptor (CAR) T cell therapy, but clinical success is lacking.
We developed 3P14HLh28Z, a novel CD33-directed CD28/CD3Z-based CAR T cell derived from a high-affinity binder obtained through membrane-proximal fragment immunization in humanized mice.
We found that immunization exclusively with the membrane-proximal domain of CD33 is necessary for identification of membrane-proximal binders in humanized mice. Compared with clinically validated lintuzumab-based CAR T cells targeting distal CD33 epitopes, 3P14HLh28Z showed enhanced in vitro functionality as well as superior tumor control and increased overall survival in both low antigen density and clinically relevant patient-derived xenograft models. Increased activation and enhanced polyfunctionality led to enhanced efficacy.
Showing for the first time that a membrane-proximal CAR is superior to a membrane-distal one in the setting of CD33 targeting, our results demonstrate the rationale for targeting membrane-proximal epitopes with high-affinity binders. We also demonstrate the importance of optimizing CAR T cells for functionality in settings of both low antigen density and clinically relevant patient-derived models. | [
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"the membrane-proximal domain",
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"3P14HLh28Z",
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] | [
"Adoptive cell therapy - ACT",
"Chimeric antigen receptor - CAR",
"Immunotherapy",
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"T cell"
] | 0 | 10.1136/jitc-2024-009013
10.1002/ajh.25162
10.3389/fonc.2020.00849
10.3390/ijms22042150
10.1158/2159-8290.CD-19-0945
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10.1182/blood-2018-01-828343
10.1158/1078-0432.CCR-10-1280
10.1158/2326-6066.CIR-13-0006
10.1038/s41375-021-01232-2
10.1016/j.ccell.2017.09.004
10.1073/pnas.1819992116
10.1016/j.cell.2018.05.013
10.1158/1078-0432.CCR-12-3115
10.3324/haematol.2018.202069
10.1200/JCO.2016.71.2513
10.1182/blood-2017-08-802157
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10.1016/j.tranon.2021.101070 | [
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"Memorial Sloan Kettering Cancer Center, New York, New York, USA.",
"Memorial Sloan Kettering Cancer Center, New York, New York, USA.",
"Memorial Sloan Kettering Cancer Center, New York, New York, USA.",
"Memorial Sloan Kettering Cancer Center, New York, New York, USA.",
"Memorial Sloan Kettering Cancer Center, New York, New York, USA.",
"Memorial Sloan Kettering Cancer Center, New York, New York, USA.",
"Memorial Sloan Kettering Cancer Center, New York, New York, USA.",
"Memorial Sloan Kettering Cancer Center, New York, New York, USA.",
"Memorial Sloan Kettering Cancer Center, New York, New York, USA.",
"Memorial Sloan Kettering Cancer Center, New York, New York, USA.",
"Memorial Sloan Kettering Cancer Center, New York, New York, USA.",
"Memorial Sloan Kettering Cancer Center, New York, New York, USA.",
"Memorial Sloan Kettering Cancer Center, New York, New York, USA.",
"Memorial Sloan Kettering Cancer Center, New York, New York, USA.",
"Memorial Sloan Kettering Cancer Center, New York, New York, USA.",
"Memorial Sloan Kettering Cancer Center, New York, New York, USA.",
"Memorial Sloan Kettering Cancer Center, New York, New York, USA.",
"Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA [email protected].",
"Memorial Sloan Kettering Cancer Center, New York, New York, USA."
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] | [] | 7.971613 | 6.114595 |
38771996 | 957 | State-of-the-Art Advancements in Gastroesophageal Cancer Treatment: Harnessing Biomarkers for Precision Care. | Gastroesophageal cancers (GECs) represent a significant clinical challenge. For early resectable GEC, the integration of immune checkpoint inhibitors into the perioperative chemotherapy and chemoradiation treatment paradigms are being explored and showing promising results. Frontline management of metastatic GEC is exploring the role of targeted therapies beyond PD-1 inhibitors, including anti-human epidermal growth factor receptor 2 agents, Claudin 18.2 inhibitors, and FGFR2 inhibitors, which have shown considerable efficacy in recent trials. Looking ahead, ongoing trials and emerging technologies such as bispecific antibodies, antibody-drug conjugates, and adoptive cell therapies like chimeric antigen receptor T cells are expected to define the future of GEC management. These advancements signify a paradigm shift toward personalized and immunotherapy-based approaches, offering the potential for improved outcomes and reduced toxicity for patients with GEC. | [
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] | 2024-05-21 | 1 | 38771996 | [
"immune checkpoint inhibitors",
"FGFR2 inhibitors",
"chimeric antigen receptor T cells",
"GEC management",
"adoptive cell therapies",
"metastatic GEC",
"early resectable GEC",
"chemoradiation treatment paradigms",
"GEC",
"bispecific antibodies",
"targeted therapies",
"ongoing trials",
"improved outcomes",
"anti-human epidermal growth factor receptor 2 agents",
"emerging technologies",
"recent trials",
"reduced toxicity",
"considerable efficacy",
"Frontline management",
"GECs",
"promising results",
"Claudin 18.2 inhibitors",
"cancers",
"Claudin",
"antibody-drug conjugates",
"FGFR2",
"a significant clinical challenge",
"patients",
"a paradigm shift",
"PD-1 inhibitors"
] | [] | 0 | 10.1200/EDBK_431060 | [
"Balmaceda",
"Petrillo",
"Krishnan",
"Zhao",
"Kim",
"Klute",
"Sundar"
] | [
"Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO.",
"Medical Oncology Unit, Ospedale del Mare, Naples, Italy.",
"Division of Oncology and Hematology, Department of Medicine, University of Nebraska Medical Center, Omaha, NB.",
"Yong Loo Lin School of Medicine, National University of Singapore, Singapore.\nDepartment of Hematology-Oncology, National University Cancer Institute, Singapore.\nDepartment of Medicine, National University Hospital, Singapore, Singapore.",
"Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO.",
"Division of Oncology and Hematology, Department of Medicine, University of Nebraska Medical Center, Omaha, NB.",
"Yong Loo Lin School of Medicine, National University of Singapore, Singapore.\nDepartment of Hematology-Oncology, National University Cancer Institute, Singapore."
] | [
"38771996"
] | [] | 11.174145 | 4.897997 |
38771986 | 958 | Phase I Trial of GD2.CART Cells Augmented With Constitutive Interleukin-7 Receptor for Treatment of High-Grade Pediatric CNS Tumors. | T cells modified with chimeric antigen receptors (CARTs) have demonstrated efficacy for hematologic malignancies; however, benefit for patients with CNS tumors has been limited. To enhance T cell activity against GD2+ CNS malignancies, we modified GD2-directed CART cells (GD2.CARTs) with a constitutively active interleukin (IL)-7 receptor (C7R-GD2.CARTs).
Patients age 1-21 years with H3K27-altered diffuse midline glioma (DMG) or other recurrent GD2-expressing CNS tumors were eligible for this phase I trial (ClinicalTrials.gov identifier: NCT04099797). All subjects received standard-of-care adjuvant radiation therapy or chemotherapy before study enrollment. The first treatment cohort received GD2.CARTs alone (1 × 10
Eleven patients (age 4-18 years) received therapy without dose-limiting toxicity. The GD2.CART cohort did not experience toxicity, but had disease progression after brief improvement of residual neurologic deficits (≤3 weeks). The C7R-GD2.CART cohort developed grade 1 tumor inflammation-associated neurotoxicity in seven of eight (88%) cases, controllable with anakinra. Cytokine release syndrome was observed in six of eight (75%, grade 1 in all but one patient) and associated with increased circulating IL-6 and IP-10 (
Intravenous GD2.CARTs with and without C7R were well tolerated. Patients treated with C7R-GD2.CARTs exhibited transient improvement of neurologic deficits and increased circulating cytokines/chemokines. Treatment with C7R-GD2.CARTs represents a novel approach warranting further investigation for children with these incurable CNS cancers. | [
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] | [] | 0 | 10.1200/JCO.23.02019
10.1200/PO.20.00375 | [
"Lin",
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"Ruggieri",
"Zhang",
"Mehta",
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"Blaney",
"Parsons",
"Brenner",
"Heslop",
"Rooney",
"Omer"
] | [
"Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX.\nDan L Duncan Comprehensive Cancer Center, Houston, TX.",
"Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX.",
"Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX.",
"Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX.",
"Department of Neurosurgery, Baylor College of Medicine, Houston, TX.",
"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX.",
"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX.",
"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX.",
"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX.",
"Department of Pathology, Baylor College of Medicine, Houston, TX.",
"Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX.\nCenter for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX.",
"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX.\nDepartment of Radiology, Brigham and Women's Hospital, Boston, MA.",
"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX.",
"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX.\nDepartment of Medicine, Baylor College of Medicine, Houston, TX.",
"Department of Pediatrics Heme-Onc and Bone Marrow Transplantation, Children's Hospital Colorado Center for Cancer and Blood Disorders, University of Colorado Anschutz Medical Campus, Denver, CO.",
"Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX.",
"Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX.",
"Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX.\nDan L Duncan Comprehensive Cancer Center, Houston, TX.",
"Dan L Duncan Comprehensive Cancer Center, Houston, TX.\nCenter for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX.\nDepartment of Medicine, Baylor College of Medicine, Houston, TX.",
"Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX.\nCenter for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX.",
"Department of Radiology, Baylor College of Medicine, Houston, TX.",
"Department of Pathology, Baylor College of Medicine, Houston, TX.",
"Dan L Duncan Comprehensive Cancer Center, Houston, TX.\nDepartment of Pathology, Baylor College of Medicine, Houston, TX.",
"Department of Neurosurgery, Baylor College of Medicine, Houston, TX.",
"Department of Neurology, Baylor College of Medicine, Houston, TX.",
"Department of Neurosurgery, Baylor College of Medicine, Houston, TX.",
"Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX.\nDan L Duncan Comprehensive Cancer Center, Houston, TX.",
"Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX.\nDan L Duncan Comprehensive Cancer Center, Houston, TX.",
"Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX.\nDan L Duncan Comprehensive Cancer Center, Houston, TX.",
"Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX.\nDan L Duncan Comprehensive Cancer Center, Houston, TX.\nCenter for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX.\nDepartment of Medicine, Baylor College of Medicine, Houston, TX.",
"Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX.\nDan L Duncan Comprehensive Cancer Center, Houston, TX.\nCenter for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX.\nDepartment of Medicine, Baylor College of Medicine, Houston, TX.",
"Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX.\nDan L Duncan Comprehensive Cancer Center, Houston, TX.\nCenter for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX.",
"Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX.\nDan L Duncan Comprehensive Cancer Center, Houston, TX.\nCenter for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX."
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38770902 | 959 | Anti-BCMA CAR-T cell-based therapies and bispecific antibodies in the immunotherapy era: are we ready for this? | Therapeutic strategies against multiple myeloma (MM) have evolved dramatically in recent decades, with unprecedent results in the treatment landscape, culminating in the recent incorporation of novel agents in the anti-myeloma armamentarium.
BCMA represents one of the most promising targets in MM and currently available immune approaches, either approved or under active investigation, are clearly showing their greater potential over standard regimens. In this context, immunotherapies based on chimeric antigen receptor (CAR)-engineered T-cells and bispecific antibodies (BsAbs) have taken center stage, being the ones that are yielding the most promising results in clinical trials. This review focuses on the current landscape of BsAbs and CAR-T, summarizing the latest advances and possible future developments.
CAR-T and BsAbs anti-BCMA strategies represent breakthrough therapies against MM. However, their inclusion in clinical practice is almost feared, due to the associated limitations, some of which have been addressed here. Meanwhile, all the efforts should be focused on individualizing and choosing the most suitable candidates for each treatment and to understand how to combine, or sequence, these therapies to improve efficacy and minimize toxicity, especially for those patients with limited available treatment options. | [
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] | 2024-05-21 | 1 | 38770902 | [
"limited available treatment options",
"chimeric antigen receptor",
"recent decades",
"unprecedent results",
"clinical practice",
"BsAbs",
"MM",
"breakthrough therapies",
"active investigation",
"possible future developments",
"Therapeutic strategies",
"bispecific antibodies",
"clinical trials",
"center stage",
"novel agents",
"multiple myeloma",
"CAR-T and BsAbs anti-BCMA strategies",
"standard regimens",
"the anti-myeloma armamentarium",
"the treatment landscape",
"toxicity",
"efficacy",
"sequence",
"currently available immune approaches",
"immunotherapies",
"CAR)-engineered T-cells",
"the recent incorporation",
"CAR-T",
"the current landscape",
"BCMA"
] | [
"B-cell maturation antigen",
"bispecific antibodies",
"chimeric antigen receptor T cells therapy",
"immunotherapy",
"multiple myeloma"
] | 0 | 10.1080/17474086.2024.2357274 | [
"Martino",
"Gamberi",
"Antonioli",
"Aquino",
"Della Pepa",
"Malerba",
"Mangiacavalli",
"Pezzatti",
"Bringhen",
"Zamagni"
] | [
"Stem Cell Transplantation and Cellular Therapies Unit (CTMO), Grande Ospedale Metropolitano \"Bianchi-Melacrino-Morelli\", Reggio Calabria, Italy.",
"Azienda USL - IRCCS di Reggio Emilia, Reggio Emilia, Reggio Emilia, Italy.",
"Hematology Department, Careggi Hospital, Florence, Italy.",
"Hematology and Hematopoietic Stem Cell Transplantation Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.",
"Hematology Unit, Department of Clinical Medicine and Surgery, University of Naples \"Federico II\", Naples, Italy.",
"Haematology and Haematopoietic Stem Cell Transplant Center, AST, Pesaro Urbino, Pesaro, Italy.",
"Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.",
"Department of Haematology, San Gerardo Hospital, Monza, MB, Italy.",
"SSD Clinical trial in oncoematologia e mieloma multiplo, Dipartimento di Oncologia, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.",
"IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \"Seràgnoli\", Bologna, Italy.\nDipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy."
] | [
"38770902"
] | [] | 4.880672 | 6.212721 |
38769449 | 960 | Current understanding and management of CAR T cell-associated toxicities. | Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of several haematological malignancies and is being investigated in patients with various solid tumours. Characteristic CAR T cell-associated toxicities such as cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are now well-recognized, and improved supportive care and management with immunosuppressive agents has made CAR T cell therapy safer and more feasible than it was when the first regulatory approvals of such treatments were granted in 2017. The increasing clinical experience with these therapies has also improved recognition of previously less well-defined toxicities, including movement disorders, immune effector cell-associated haematotoxicity (ICAHT) and immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), as well as the substantial risk of infection in patients with persistent CAR T cell-induced B cell aplasia and hypogammaglobulinaemia. A more diverse selection of immunosuppressive and supportive-care pharmacotherapies is now being utilized for toxicity management, yet no universal algorithm for their application exists. As CAR T cell products targeting new antigens are developed, additional toxicities involving damage to non-malignant tissues expressing the target antigen are a potential hurdle. Continued prospective evaluation of toxicity management strategies and the design of less-toxic CAR T cell products are both crucial for ongoing success in this field. In this Review, we discuss the evolving understanding and clinical management of CAR T cell-associated toxicities. | [
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] | 2024-05-21 | 5 | 38769428 | [] | [] | 0 | 10.1038/s43018-024-00765-6
10.1158/2159-8290.CD-17-1319
10.1016/j.bbmt.2018.12.758
10.1136/jitc-2020-001511
10.1182/blood.2020008865
10.1172/JCI130272 | [] | [] | [
"38769428",
"29880584",
"30592986",
"33534891",
"31846439"
] | [] | 32.978188 | 7.556377 |
38768669 | 962 | Expand available targets for CAR-T therapy to overcome tumor drug resistance based on the "Evolutionary Traps". | Based on the concept of "Evolutionary Traps", targeting survival essential genes obtained during tumor drug resistance can effectively eliminate resistant cells. While, it still faces limitations. In this study, lapatinib-resistant cells were used to test the concept of "Evolutionary Traps" and no suitable target stand out because of the identified genes without accessible drug. However, a membrane protein PDPN, which is low or non-expressed in normal tissues, is identified as highly expressed in lapatinib-resistant tumor cells. PDPN CAR-T cells were developed and showed high cytotoxicity against lapatinib-resistant tumor cells in vitro and in vivo, suggesting that CAR-T may be a feasible route for overcoming drug resistance of tumor based on "Evolutionary Trap". To test whether this concept is cell line or drug dependent, we analyzed 21 drug-resistant tumor cell expression profiles reveal that JAG1, GPC3, and L1CAM, which are suitable targets for CAR-T treatment, are significantly upregulated in various drug-resistant tumor cells. Our findings shed light on the feasibility of utilizing CAR-T therapy to treat drug-resistant tumors and broaden the concept of the "Evolutionary Trap". | [
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] | 2024-05-21 | 1 | 38768669 | [
"resistant cells",
"tumor drug resistance",
"drug resistance",
"various drug-resistant tumor cells",
"cell line",
"accessible drug",
"tumor",
"lapatinib-resistant tumor cells",
"drug-resistant tumors",
"suitable targets",
"21 drug-resistant tumor cell expression profiles",
"lapatinib-resistant cells",
"survival essential genes",
"PDPN CAR-T cells",
"normal tissues",
"high cytotoxicity",
"PDPN",
"CAR-T treatment",
"limitations",
"light",
"CAR-T therapy",
"JAG1",
"GPC3",
"\"Evolutionary Traps",
"L1CAM",
"CAR-T",
"vivo",
"no suitable target",
"the identified genes",
"\"Evolutionary Trap"
] | [
"CAR-T therapy",
"Cancer, Drug resistance",
"Evolutionary Trap",
"Lapatinib (PubChem CID: 208908)",
"PDPN"
] | 0 | 10.1016/j.phrs.2024.107221 | [
"Wang",
"Wang",
"Liao",
"Zhao",
"Hou",
"Li",
"Guan",
"Jin",
"Ma",
"Liu",
"Zheng",
"Shi"
] | [
"Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China.",
"Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China.",
"Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China.",
"Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China.",
"College of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China.",
"Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China.",
"Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China.",
"Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China.",
"Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China.",
"Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China. Electronic address: [email protected].",
"Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China. Electronic address: [email protected].",
"Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China. Electronic address: [email protected]."
] | [
"38768669"
] | [] | 9.421995 | 5.22978 |
38768428 | 963 | Clinical evaluation and determinants of response to HBI0101 (BCMA CART) therapy in relapsed/refractory multiple myeloma. | HBI0101 is an academic chimeric antigen receptor T-cell (CART)-targeted to B-cell maturation antigen (BCMA) for the treatment of relapsed and refractory multiple myeloma (R/RMM) and light chain amyloidosis. Herein, we present the phase 1b/2 results of 50 heavily pretreated patients with R/RMM dosed with 800 × 106 CART cells. Inclusion criteria were relatively permissive (i.e., performance status and baseline organ function) and consequently, approximately half of the enrolled patients would have been ineligible for pivotal clinical trials. The median time elapsed from patient enrollment until CART delivery was 25 days (range, 14-65). HBI0101-related toxicities included grade 1 to 3 cytokine release syndrome, grade 3 to 4 hematologic toxicities, and grade 1 to 2 immune effector cell-associated neurotoxicity syndrome. Responses were achieved in 90% of the patients, 56% achieved stringent and complete response, and 70% reached a minimal residual disease negativity. Within a median follow-up of 12.3 months, the median progression-free survival (PFS) was 11.0 months (95% confidence interval [CI], 6.2-14.6), and the overall survival was not reached (95% CI, 13.3 to not reached). Multivariable analysis on patient/disease and CART-related characteristics revealed that high-risk cytogenetic, extramedullary disease, and increased number of effector-memory T cells in CART products were independently associated with inferior PFS. In conclusion, comprehensive analyses of the parameters affecting the response to CART therapy are essential for improving patients' outcome. This trial was registered at www.ClinicalTrials.gov as #NCT04720313. | [
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] | 2024-05-20 | 40 | 38768428 | [
"CART therapy",
"CART products",
"baseline organ function",
"pivotal clinical trials",
"patient enrollment",
"CART delivery",
"Responses",
"RMM",
"comprehensive analyses",
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"relapsed and refractory multiple myeloma",
"95% confidence interval",
"BCMA",
"HBI0101-related toxicities",
"HBI0101",
"stringent and complete response",
"NCT04720313"
] | [] | 0 | 10.1182/bloodadvances.2024012967 | [
"Kfir-Erenfeld",
"Asherie",
"Lebel",
"Vainstein",
"Assayag",
"Dubnikov Sharon",
"Grisariu",
"Avni",
"Elias",
"Alexander-Shani",
"Bessig",
"Shehadeh",
"Ishtay",
"Zelmanovich",
"Zimran",
"Pick",
"Roziner",
"Kenett",
"Cohen",
"Avivi",
"Cohen",
"Gatt",
"Stepensky"
] | [
"Department of Bone Marrow Transplantation and Cancer Immunotherapy, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.",
"Department of Bone Marrow Transplantation and Cancer Immunotherapy, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.",
"Department of Hematology, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.",
"Department of Hematology, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.",
"Department of Bone Marrow Transplantation and Cancer Immunotherapy, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.",
"Department of Bone Marrow Transplantation and Cancer Immunotherapy, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.",
"Department of Bone Marrow Transplantation and Cancer Immunotherapy, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.",
"Department of Bone Marrow Transplantation and Cancer Immunotherapy, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.",
"Department of Bone Marrow Transplantation and Cancer Immunotherapy, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.",
"Department of Bone Marrow Transplantation and Cancer Immunotherapy, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.",
"Department of Bone Marrow Transplantation and Cancer Immunotherapy, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.",
"Department of Bone Marrow Transplantation and Cancer Immunotherapy, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.",
"Department of Bone Marrow Transplantation and Cancer Immunotherapy, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.",
"Department of Bone Marrow Transplantation and Cancer Immunotherapy, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.",
"Department of Hematology, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.",
"Department of Hematology, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.",
"Department of Communication Disorders, Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel.",
"Kenett-Preminger Associates Ltd, Samuel Neaman Institute, Technion, Haifa, Israel.",
"Department of Hematology, Faculty of Medicine, Tel Aviv Medical Center, Tel Aviv University, Tel Aviv, Israel.",
"Department of Hematology, Faculty of Medicine, Tel Aviv Medical Center, Tel Aviv University, Tel Aviv, Israel.",
"Laboratory of Tumor Immunology and Immunotherapy, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.",
"Department of Hematology, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.",
"Department of Bone Marrow Transplantation and Cancer Immunotherapy, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel."
] | [
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38767611 | 964 | Chimeric Antigen Receptor T Cell with an Inducible Caspase-9 Suicide Gene Eradicates Uveal Melanoma Liver Metastases via B7-H3 Targeting. | Uveal melanoma (UM) is the most common intraocular malignant tumor. Despite successful treatment of the primary tumor, about 50% of patients will recur with systemic diseases for which there are no effective treatment strategies. Here we investigated the preclinical efficacy of a chimeric antigen receptor (CAR) T-cell-based immunotherapy targeting B7-H3.
B7-H3 expression on primary and metastatic human UM samples and cell lines was assessed by RNA sequencing, flow cytometry, and immunohistochemistry. Antitumor activity of CAR T cells targeting B7-H3 was tested in vitro with UM cell lines, patient-derived organotypic tumor spheroids from patients with metastatic UM, and in immunodeficient and humanized murine models.
B7-H3 is expressed at high levels in >95% UM tumor cells in vitro and in vivo. We generated a B7-H3 CAR with an inducible caspase-9 (iCas9) suicide gene controlled by the chemical inducer of dimerization AP1903, which effectively kills UM cells in vitro and eradicates UM liver metastases in murine models. Delivery of iCas9.B7-H3 CAR T cells in experimental models of UM liver metastases demonstrates a durable antitumor response, even upon tumor rechallenge or in the presence of a significant metastatic disease burden. We demonstrate effective iCas9.B7-H3 CAR T-cell elimination in vitro and in vivo in response to AP1903. Our studies demonstrate more effective tumor suppression with iCas9.B7-H3 CAR T cells as compared to a B7-H3-targeted humanized monoclonal antibody.
These studies support a phase I clinical trial with iCas9.B7-H3 CAR T cells to treat patients with metastatic UM. | [
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] | 2024-05-20 | 48 | 38767611 | [
"UM cells",
"UM cell lines",
"CAR T cells",
"metastatic UM",
"cell lines",
"UM liver metastases",
"UM",
"iCas9.B7-H3 CAR T cells",
"tumor rechallenge",
"effective iCas9.B7-H3 CAR T-cell elimination",
"primary and metastatic human UM samples",
"humanized murine models",
"iCas9.B7-H3 CAR T",
"B7-H3 CAR",
">95% UM tumor cells",
"iCas9.B7-H3 CAR",
"patients",
"patient-derived organotypic tumor spheroids",
"murine models",
"systemic diseases",
"dimerization AP1903",
"experimental models",
"B7-H3 expression",
"flow cytometry",
"more effective tumor suppression",
"B7-H3",
"successful treatment",
"high levels",
"a significant metastatic disease burden",
"CAR) T-cell-based immunotherapy"
] | [] | 0 | 10.1158/1078-0432.CCR-24-0071 | [
"Ventin",
"Cattaneo",
"Arya",
"Jia",
"Gelmi",
"Sun",
"Maggs",
"Ksander",
"Verdijk",
"Boland",
"Jenkins",
"Haq",
"Jager",
"Wang",
"Ryeom",
"Ferrone"
] | [
"Department of Surgery, Division of Gastrointestinal and Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.",
"Department of Surgery, Division of Gastrointestinal and Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.",
"Department of Surgery, Division of Gastrointestinal and Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.",
"Department of Surgery, Division of Gastrointestinal and Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.",
"Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.",
"Department of Medicine, Mass General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.",
"Department of Surgery, Division of Gastrointestinal and Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.",
"Department of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts.",
"Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.\nDepartment of Pathology, Section Ophtalmic Pathology, Erasmus Medical Center, Rotterdam, the Netherlands.",
"Department of Surgery, Division of Gastrointestinal and Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.",
"Department of Medicine, Mass General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.\nBroad Institute of MIT and Harvard, Cambridge, Massachusetts.",
"Broad Institute of MIT and Harvard, Cambridge, Massachusetts.\nDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.",
"Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.\nDepartment of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts.",
"Department of Surgery, Division of Gastrointestinal and Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.",
"Department of Surgery, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York.",
"Department of Surgery, Division of Gastrointestinal and Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.\nDepartment of Surgery, Cedars Sinai Medical Center, Los Angeles, California."
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] | [] | 10.07007 | 6.7 |
38766710 | 965 | Beyond CAR T cells: exploring alternative cell sources for CAR-like cellular therapies. | Chimeric antigen receptor (CAR)-T cell therapy has led to remarkable clinical outcomes in the treatment of hematological malignancies. However, challenges remain, such as limited infiltration into solid tumors, inadequate persistence, systemic toxicities, and manufacturing insufficiencies. The use of alternative cell sources for CAR-based therapies, such as natural killer cells (NK), macrophages (MΦ), invariant Natural Killer T (iNKT) cells, γδT cells, neutrophils, and induced pluripotent stem cells (iPSC), has emerged as a promising avenue. By harnessing these cells' inherent cytotoxic mechanisms and incorporating CAR technology, common CAR-T cell-related limitations can be effectively mitigated. We herein present an overview of the tumoricidal mechanisms, CAR designs, and manufacturing processes of CAR-NK cells, CAR-MΦ, CAR-iNKT cells, CAR-γδT cells, CAR-neutrophils, and iPSC-derived CAR-cells, outlining the advantages, limitations, and potential solutions of these therapeutic strategies. | [
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"Division of Clinical Pharmacology, University Hospital, LMU Munich, Lindwurmstr. 2a, 80337 Munich, Germany.",
"Division of Clinical Pharmacology, University Hospital, LMU Munich, Lindwurmstr. 2a, 80337 Munich, Germany.\nDepartment of Medicine III, University Hospital, LMU Munich, Marchioninstr. 15, 81377 Munich, Germany.\nBavarian Cancer Research Center (BZKF), LMU Munich, Pettenkoferstr. 8a, 80336 Munich, Germany.",
"Division of Clinical Pharmacology, University Hospital, LMU Munich, Lindwurmstr. 2a, 80337 Munich, Germany.",
"Department of Medicine III, University Hospital, LMU Munich, Marchioninstr. 15, 81377 Munich, Germany.\nBavarian Cancer Research Center (BZKF), LMU Munich, Pettenkoferstr. 8a, 80336 Munich, Germany.\n74939 German Cancer Consortium (DKTK), Partner Site Munich, A Partnership Between DKFZ and University Hospital of the LMU , Marchioninstr. 15, 81377 Munich, Germany.\nCancer and Immunometabolism Research Group, 74939 Gene Center LMU , Feodor-Lynen Str. 25, 81377 Munich, Germany.",
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] | 2024-05-20 | 1 | 38766252 | [
"primary human T cells",
"solid tumor efficacy",
"B cell malignancies",
"anti-tumor functions",
"Chimeric antigen receptor therapies",
"solid tumors",
"potent efficacy",
"CARPOOL",
"CARs",
"selections",
"our pooled screening platform",
"the discovery",
"a library",
"1.3×10",
"We",
"we"
] | [] | 0 | 10.1101/2024.04.04.586240 | [
"Gordon",
"Perez",
"Garmilla",
"Lam",
"Aw",
"Datta",
"Lauffenburger",
"Pavesi",
"Birnbaum"
] | [
null,
null,
null,
null,
null,
null,
null,
null,
null
] | [
"38766252"
] | [] | 9.094355 | 4.600355 |
38765003 | 967 | Case report: Rapid resolution of grade IV ICANS after first line intrathecal chemotherapy with methotrexate, cytarabine and dexamethasone. | Corticosteroid therapy is the mainstay of immune effector cell-associated neurotoxicity syndrome (ICANS) management, although its use has been associated with worse overall survival (OS) and progression-free survival (PFS) after chimeric antigen receptor T-cell (CAR-T cell) therapy. Many options are being investigated for prophylaxis and management. Accumulating evidence supports the use of intrathecal (IT) chemotherapy for the management of high-grade ICANS. Here, we describe a case of a patient with stage IV Primary mediastinal B-cell lymphoma (PMBCL) successfully treated with IT methotrexate, cytarabine, and dexamethasone as first-line therapy for CD19 CAR-T cell-associated grade IV ICANS. The stable and rapid resolution of ICANS to grade 0 allowed us to discontinue systemic corticosteroid use, avoiding CAR-T cells ablation and ensuring preservation of CAR-T cell function. The described patient achieved a complete radiologic and clinical response to CD19 CAR-T cell therapy and remains disease-free after 9 months. This case demonstrates a promising example of how IT chemotherapy could be used as first-line treatment for the management of high-grade ICANS. | [
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10.21873/anticanres.15876 | [
"Katsin",
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"Serada",
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"Department of Hematology, Vitebsk Regional Clinical Cancer Centre, Vitebsk, Belarus.",
"Laboratory of Genetic Biotechnologies, Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus.",
"Laboratory of Genetic Biotechnologies, Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus.",
"Laboratory of Genetic Biotechnologies, Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus.",
"Department of Hematology, Vitebsk Regional Clinical Cancer Centre, Vitebsk, Belarus.",
"Department of Hematology, Vitebsk Regional Clinical Cancer Centre, Vitebsk, Belarus.",
"Department of Hematology, Vitebsk Regional Clinical Cancer Centre, Vitebsk, Belarus.",
"Laboratory of Molecular Diagnostics and Biotechnology, Institute of Bioorganic Chemistry of the National Academy of Sciences of Belarus, Minsk, Belarus."
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38763321 | 968 | Altered cancer metabolism and implications for next-generation CAR T-cell therapies. | This review critically examines the evolving landscape of chimeric antigen receptor (CAR) T-cell therapy in treating solid tumors, with a particular focus on the metabolic challenges within the tumor microenvironment. CAR T-cell therapy has demonstrated remarkable success in hematologic malignancies, yet its efficacy in solid tumors remains limited. A significant barrier is the hostile milieu of the tumor microenvironment, which impairs CAR T-cell survival and function. This review delves into the metabolic adaptations of cancer cells and their impact on immune cells, highlighting the competition for nutrients and the accumulation of immunosuppressive metabolites. It also explores emerging strategies to enhance CAR T-cell metabolic fitness and persistence, including genetic engineering and metabolic reprogramming. An integrated approach, combining metabolic interventions with CAR T-cell therapy, has the potential to overcome these constraints and improve therapeutic outcomes in solid tumors. | [
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] | 2024-05-20 | 1 | 38763321 | [
"cancer cells",
"immune cells",
"solid tumors",
"CAR T-cell therapy",
"CAR T-cell metabolic fitness",
"CAR T-cell survival",
"metabolic reprogramming",
"chimeric antigen receptor",
"CAR) T-cell therapy",
"metabolic interventions",
"genetic engineering",
"hematologic malignancies",
"remarkable success",
"therapeutic outcomes",
"emerging strategies",
"immunosuppressive metabolites",
"nutrients",
"the tumor microenvironment",
"persistence",
"the metabolic adaptations",
"the metabolic challenges",
"function",
"the evolving landscape",
"the hostile milieu",
"a particular focus",
"An integrated approach",
"A significant barrier",
"the competition",
"This review",
"the accumulation"
] | [
"CAR T-cell therapy",
"CRISPR Cas systems",
"Immunotherapy",
"Metabolism",
"Solid tumors",
"Tumor microenvironment"
] | 0 | 10.1016/j.pharmthera.2024.108667 | [
"Ramapriyan",
"Vykunta",
"Vandecandelaere",
"Richardson",
"Sun",
"Curry",
"Choi"
] | [
"Brain Tumor Immunotherapy Laboratory, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: [email protected].",
"Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; Medical Scientist Training Program, School of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.",
"Brain Tumor Immunotherapy Laboratory, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.",
"Brain Tumor Immunotherapy Laboratory, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.",
"Brain Tumor Immunotherapy Laboratory, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.",
"Brain Tumor Immunotherapy Laboratory, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.",
"Brain Tumor Immunotherapy Laboratory, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: [email protected]."
] | [
"38763321"
] | [] | 10.152699 | 4.9915 |
38762281 | 969 | Recent advances in CAR T-cell engineering using synthetic biology: Paving the way for next-generation cancer treatment. | This book chapter highlights a comprehensive exploration of the transformative innovations in the field of cancer immunotherapy. CAR (Chimeric Antigen Receptor) T-cell therapy represents a groundbreaking approach to treat cancer by reprogramming a patient immune cells to recognize and destroy cancer cells. This chapter underscores the critical role of synthetic biology in enhancing the safety and effectiveness of CAR T-cell therapies. It begins by emphasizing the growing importance of personalized medicine in cancer treatment, emphasizing the shift from one-size-fits-all approaches to patient-specific solutions. Synthetic biology, a multidisciplinary field, has been instrumental in customizing CAR T-cell therapies, allowing for fine-tuned precision and minimizing unwanted side effects. The chapter highlights recent advances in gene editing, synthetic gene circuits, and molecular engineering, showcasing how these technologies are optimizing CAR T-cell function. In summary, this book chapter sheds light on the remarkable progress made in the development of CAR T-cell therapies using synthetic biology, providing hope for cancer patients and hinting at a future where highly personalized and effective cancer treatments are the norm. | [
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] | 2024-05-19 | 1 | 38762281 | [
"cancer cells",
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"cancer",
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] | [
"CAR T-Cell",
"Cancer",
"Synthetic biology",
"Therapy",
"Treatment"
] | 0 | 10.1016/bs.apcsb.2024.02.003 | [
"Dey",
"Devender",
"Rani",
"Pandey"
] | [
"CSO Department, Cellworks Research India Pvt Ltd, Bengaluru, Karnataka, India.",
"Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, India.",
"ICAR, National Institute of Veterinary Epidemiology and Disease Informatics, Bengaluru, Karnataka, India.",
"Department of Medical Biochemistry and Biophysics, Karolinska Institute, Solna, Sweden. Electronic address: [email protected]."
] | [
"38762281"
] | [] | 9.583717 | 3.798926 |
38762272 | 970 | Current status and future prospective of breast cancer immunotherapy. | The immune system is complicated, interconnected, and offers a powerful defense system that protects its host from foreign pathogens. Immunotherapy involves boosting the immune system to kill cancer cells, and nowadays, is a major emerging treatment for cancer. With the advances in our understanding of the immunology of cancer, there has been an explosion of studies to develop and evaluate therapies that engage the immune system in the fight against cancer. Nevertheless, conventional therapies have been effective in reducing tumor burden and prolonging patient life, but the overall efficacy of these treatment regimens has been somewhat mixed and often with severe side effects. A common reason for this is the activation of molecular mechanisms that lead to apoptosis of anti-tumor effector cells. The competency to block tumor escape entirely depends on our understanding of the cellular and molecular pathways which operate in the tumor microenvironment. Numerous strategies have been developed for activating the immune system to kill tumor cells. Breast cancer is one of the major causes of cancer death in women, and is characterized by complex molecular and cellular events that closely intertwine with the host immune system. In this regard, predictive biomarkers of immunotherapy, use of nanotechnology, personalized cancer vaccines, antibodies to checkpoint inhibitors, engineered chimeric antigen receptor-T cells, and the combination with other therapeutic modalities have transformed cancer therapy and optimized the therapeutic effect. In this chapter, we will offer a holistic view of the different therapeutic modalities and recent advances in immunotherapy. Additionally, we will summarize the recent advances and future prospective of breast cancer immunotherapies, as a case study. | [
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] | 2024-05-19 | 1 | 38762272 | [
"cancer cells",
"breast cancer immunotherapies",
"cancer therapy",
"Breast cancer",
"cancer vaccines",
"cancer death",
"cancer",
"tumor cells",
"anti-tumor effector cells",
"other therapeutic modalities",
"tumor burden",
"tumor escape",
"molecular mechanisms",
"recent advances",
"conventional therapies",
"Immunotherapy",
"immunotherapy",
"therapies",
"the host immune system",
"severe side effects",
"patient life",
"The immune system",
"the immune system",
"future prospective",
"complex molecular and cellular events",
"predictive biomarkers",
"a powerful defense system",
"studies",
"the different therapeutic modalities",
"foreign pathogens"
] | [
"Breast cancer",
"Cancer immunotherapy",
"Cell and gene therapy",
"Immune checkpoint inhibitors",
"Mathematical modeling",
"Vaccines"
] | 0 | 10.1016/bs.apcsb.2023.12.006 | [
"Rathore",
"Chirmule",
"Dash",
"Chowdhury"
] | [
"Indian Institute of Technology, Delhi, India. Electronic address: [email protected].",
"Indian Institute of Technology, Delhi, India.",
"Indian Institute of Technology, Delhi, India.",
"Indian Institute of Technology, Delhi, India."
] | [
"38762272"
] | [] | 10.826048 | 4.312109 |
38762269 | 971 | Engineered CAR-T cells: An immunotherapeutic approach for cancer treatment and beyond. | Chimeric Antigen Receptor (CAR) T cell therapy is a type of adoptive immunotherapy that offers a promising avenue for enhancing cancer treatment since traditional cancer treatments like chemotherapy, surgery, and radiation therapy have proven insufficient in completely eradicating tumors, despite the relatively positive outcomes. It has been observed that CAR-T cell therapy has shown promising results in treating the majority of hematological malignancies but also have a wide scope for other cancer types. CAR is an extra receptor on the T-cell that helps to increase and accelerate tumor destruction by efficiently activating the immune system. It is made up of three domains, the ectodomain, transmembrane, and the endodomain. The ectodomain is essential for antigen recognition and binding, whereas the co-stimulatory signal is transduced by the endodomain. To date, the Food and Drug Administration (FDA) has granted approval for six CAR-T cell therapies. However, despite its remarkable success, CAR-T therapy is associated with numerous adverse events and has certain limitations. This chapter focuses on the structure and function of the CAR domain, various generations of CAR, and the process of CAR-T cell development, adverse effects, and challenges in CAR-T therapy. CAR-T cell therapy also has scopes in other disease conditions which include systemic lupus erythematosus, multiple sclerosis, and myocardial fibrosis, etc. | [
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] | 2024-05-19 | 1 | 38762269 | [
"radiation therapy",
"CAR-T cell therapy",
"CAR",
"other cancer types",
"CAR-T therapy",
"traditional cancer treatments",
"tumor destruction",
"other disease conditions",
"cancer treatment",
"systemic lupus erythematosus",
"numerous adverse events",
"CAR-T cell development",
"six CAR-T cell therapies",
"promising results",
"adverse effects",
"multiple sclerosis",
"antigen recognition",
"hematological malignancies",
"various generations",
"scopes",
"adoptive immunotherapy",
"myocardial fibrosis",
"the CAR domain",
"the co-stimulatory signal",
"binding",
"certain limitations",
"FDA",
"function",
"approval",
"chemotherapy"
] | [
"CAR-T cell",
"CD3ξ",
"Cytokine release syndrome (CRS)",
"Leukapheresis",
"Leukemia",
"ScFv",
"Tumor antigen"
] | 0 | 10.1016/bs.apcsb.2023.12.001 | [
"Khodke",
"Kumbhar"
] | [
"Department of Biological Sciences, Sunandan Divatia School of Science, SVKM's Narsee Monjee Institute of Management Studies (NMIMS) Deemed-to-be University, Mumbai, India.",
"Department of Biological Sciences, Sunandan Divatia School of Science, SVKM's Narsee Monjee Institute of Management Studies (NMIMS) Deemed-to-be University, Mumbai, India. Electronic address: [email protected]."
] | [
"38762269"
] | [] | 8.359541 | 4.408503 |
38762057 | 972 | ACT To Sustain: Adoptive Cell Therapy To Sustain Access to Non-Commercialized Genetically Modified Cell Therapies. | Genetically modified cell therapies (GMCT), particularly immune effector cells (IEC) such as chimeric receptor antigen (CAR) T cells, have shown promise in curing cancer and rare diseases after a single treatment course. Following close behind CAR T approvals are GMCT based on hematopoietic stem cells, such as products developed for hemoglobinopathies and other disorders. Academically sponsored GMCT products, often developed in academic centers without industry involvement, face challenges in sustaining access after completion of early phase studies when there is no commercial partner invested in completing registration trials for marketing applications. The American Society for Transplantation and Cellular Therapy (ASTCT) formed a task force named ACT To Sustain (Adoptive Cell Therapy to Sustain) to address the "valley of death" of academic GMCT products. This paper presents the task force's findings and considerations regarding financial sustainability of academically sponsored GMCT products in the absence of commercial development. We outline case scenarios illustrating barriers to maintaining access to promising GMCT developed by academic centers. The paper also delves into the current state of GMCT development, commercialization, and reimbursement, citing examples of abandoned products, cost estimates associated with GMCT manufacturing and real-world use of cost recovery. We propose potential solutions to address the financial, regulatory, and logistical challenges associated with sustaining access to academically sponsored GMCT products and to ensure that products with promising results do not languish in a "valley of death" due to financial or implementational barriers. The suggestions include aligning US Food and Drug Administration (FDA) designations with benefit coverage, allowing for cost recovery of certain products as a covered benefit, and engaging with regulators and policy makers to discuss alternative pathways for academic centers to provide access. We stress the importance of sustainable access to GMCT and call for collaborative efforts to develop regulatory pathways that support access to academically sponsored GMCT products. | [
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] | 0 | 10.1016/j.jtct.2024.05.010 | [
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"St Jude Children's Research Hospital, Memphis, Tennessee. Electronic address: [email protected].",
"Division of Oncology, Cell Therapy and Transplant Section, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.",
"Harvard-MIT Center for Regulatory Science, Harvard Medical School, Cellular Immunotherapy Program, Mass General Cancer Center, Boston, Massachusetts.",
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"Division of Oncology, Cell Therapy and Transplant Section, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.",
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"Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, Florida.",
"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.",
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"Department of Pediatrics, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas; Texas Children's Hospital and Texas Children's Cancer Center, Houston, Texas.",
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"UCSF Health Division of Hematology/Oncology and Helen Diller Family Comprehensive Cancer Center, San Francisco, California.",
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38761798 | 973 | The invisible hand: How epigenetics shapes CAR T cell destiny. | null | [
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] | 2024-05-19 | 22 | 38761798 | [] | [] | 0 | 10.1016/j.ymthe.2024.05.007
10.1101/2023.04.21.537859 | [
"Ali",
"Zhang",
"DiPersio"
] | [
"Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA. Electronic address: [email protected].",
"Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA; Center for Discovery and Innovation, Nutley, NJ, USA.",
"Washington University in Saint Louis, Saint Louis, MO, USA."
] | [
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] | [] | 32.922527 | 7.546298 |
38761562 | 974 | Translational insights into the genetics and immunobiology of relapsed/refractory follicular lymphoma. | Although follicular lymphoma (FL) is traditionally classified as an indolent subtype of B cell non-Hodgkin lymphoma, clinical trajectories are often diverse based on unique disease biology, and many patients will eventually experience relapse of their disease. Furthermore, progression of disease within 24 months is associated with increased mortality rates for FL. In the last five years, we have witnessed an upsurge in the commercial availability of targeted therapies for relapsed/refractory (R/R) FL, including chimeric antigen receptor-T (CAR-T) products, bispecific T cell engagers (BiTEs), epigenetic modifier therapies, and next-generation Bruton tyrosine kinase (BTK) inhibitors. Furthermore, clinical trial options have increased tremendously and now include combinatorial strategies that exert synergy against malignant germinal center B cells. Here, we provide a 2024 update of novel therapeutic agents whose development has been informed by recent advances in the genetics and immunobiology of R/R FL. Specifically, we emphasize high-value targeted therapeutics, including anti-CD3 x anti-CD20 BiTEs and adoptive T cell therapies. We discuss prospects on selection and sequencing of BiTEs and CAR-T therapies for patients with R/R FL. We underscore the principles of FL pathobiology that are paving way for future drug discovery and shed insight into therapeutic targeting within nodal basins based on our increasing understanding of the FL microenvironment. Finally, we summarize how a greater knowledge of FL immunobiology can inform risk stratification and therapy selection on a personalized basis for R/R FL in 2025. | [
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] | 2024-05-19 | 1 | 38761562 | [
"FL immunobiology",
"adoptive T cell therapies",
"FL pathobiology",
"FL",
"targeted therapies",
"therapy selection",
"B cell non-Hodgkin lymphoma",
"epigenetic modifier therapies",
"malignant germinal center B cells",
"bispecific T cell engagers",
"increased mortality rates",
"R/R FL",
"novel therapeutic agents",
"unique disease biology",
"non-Hodgkin",
"therapeutic targeting",
"future drug discovery",
"many patients",
"clinical trial options",
"clinical trajectories",
"CAR-T therapies",
"disease",
"follicular lymphoma",
"nodal basins",
"combinatorial strategies",
"recent advances",
"BiTEs",
"risk stratification",
"immunobiology",
"selection"
] | [
"Bispecific antibodies",
"CAR-T cells",
"Follicular lymphoma",
"Novel therapies"
] | 0 | 10.1016/j.leukres.2024.107519 | [
"Yaniv",
"Tanenbaum",
"Kazakova",
"Patel"
] | [
"Dept. of Medicine - Division of Hematology/Oncology, UMass Memorial Medical Center, UMass Chan Medical School, Worcester, MA, United States.",
"Dept. of Medicine - Division of Hematology/Oncology, UMass Memorial Medical Center, UMass Chan Medical School, Worcester, MA, United States.",
"Dept. of Medicine - Division of Hematology/Oncology, UMass Memorial Medical Center, UMass Chan Medical School, Worcester, MA, United States.",
"Dept. of Medicine - Division of Hematology/Oncology, UMass Memorial Medical Center, UMass Chan Medical School, Worcester, MA, United States; Center for Clinical & Translational Science, UMass Chan Medical School, Worcester, MA, United States; Cancer Biology Program, Morningside Graduate School of Biomedical Sciences, UMass Chan Medical School, Worcester, MA, United States. Electronic address: [email protected]."
] | [
"38761562"
] | [] | 6.195283 | 6.30184 |
38760566 | 975 | Bidirectional epigenetic editing reveals hierarchies in gene regulation. | CRISPR perturbation methods are limited in their ability to study non-coding elements and genetic interactions. In this study, we developed a system for bidirectional epigenetic editing, called CRISPRai, in which we apply activating (CRISPRa) and repressive (CRISPRi) perturbations to two loci simultaneously in the same cell. We developed CRISPRai Perturb-seq by coupling dual perturbation gRNA detection with single-cell RNA sequencing, enabling study of pooled perturbations in a mixed single-cell population. We applied this platform to study the genetic interaction between two hematopoietic lineage transcription factors, SPI1 and GATA1, and discovered novel characteristics of their co-regulation on downstream target genes, including differences in SPI1 and GATA1 occupancy at genes that are regulated through different modes. We also studied the regulatory landscape of IL2 (interleukin-2) in Jurkat T cells, primary T cells and chimeric antigen receptor (CAR) T cells and elucidated mechanisms of enhancer-mediated IL2 gene regulation. CRISPRai facilitates investigation of context-specific genetic interactions, provides new insights into gene regulation and will enable exploration of non-coding disease-associated variants. | [
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"T cells",
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"primary T cells",
"gene regulation",
"genetic interactions",
"non-coding elements",
"downstream target genes",
"dual perturbation gRNA detection",
"pooled perturbations",
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"the genetic interaction",
"the same cell",
"CRISPRa"
] | [] | 0 | 10.1038/s41587-024-02213-3
10.1021/acssynbio.8b00527
10.1101/gr.275607.121
10.1038/s41593-021-00862-0
10.1126/science.abj4008
10.1109/CDC.2018.8619016
10.18129/B9.bioc.motifmatchr | [
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] | [
"Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.\nDepartment of Bioengineering, Stanford University, Stanford, CA, USA.",
"Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.",
"Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.",
"Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.",
"Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.\nDepartment of Medicine, University of California, San Francisco, San Francisco, CA, USA.\nDepartment of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA.",
"Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.",
"Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.\nProgram in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA.\nCartography Biosciences, Inc., South San Francisco, CA, USA.",
"Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.\nDepartment of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA.\nUCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.",
"Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.\nDepartment of Medicine, University of California, San Francisco, San Francisco, CA, USA.\nUCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.\nParker Institute for Cancer Immunotherapy, San Francisco, CA, USA.\nInstitute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.\nDepartment of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.\nDiabetes Center, University of California, San Francisco, San Francisco, CA, USA.\nInnovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA.",
"Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA. [email protected].\nHoward Hughes Medical Institute, Stanford University, Stanford, CA, USA. [email protected]."
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38760376 | 976 | Impact of the kinetics of circulating anti-CD19 CAR-T cells and their populations on the outcome of DLBCL patients. | null | [
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] | 2024-05-18 | 16 | 38760376 | [] | [] | 0 | 10.1038/s41408-024-01065-z
10.1056/NEJMra2027612
10.1016/S1470-2045(21)00375-2
10.1056/NEJMoa2301665
10.1182/bloodadvances.2023011992
10.1158/1078-0432.CCR-22-0164
10.1182/bloodadvances.2023010364
10.1016/S1470-2045(18)30864-7
10.1038/s41591-019-0549-5
10.3389/fimmu.2015.00020
10.3389/fimmu.2014.00636
10.1038/cmi.2015.28
10.1038/nri3904
10.1016/j.jhep.2018.05.007
10.1038/s41571-022-00722-1
10.3389/fimmu.2020.01347 | [
"Martín-Martín",
"Gutiérrez-Herrero",
"Herrero-García",
"Martín García-Sancho",
"Yeguas",
"Martín-López",
"López-Corral",
"Pérez-López",
"García-Blázquez",
"Sánchez-Guijo",
"Vidriales",
"Gaipa",
null,
null,
"Orfao"
] | [
"Translational and Clinical Research Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Consejo Superior de Investigaciones Científicas (CSIC), and University of Salamanca, Salamanca, Spain.\nFlow Cytometry Service (NUCLEUS), University of Salamanca, Salamanca, Spain.\nInstitute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.\nDepartment of Medicine, University of Salamanca (Universidad de Salamanca), Salamanca, Spain.\nBiomedical Research Networking Centre Consortium of Oncology (CIBERONC), Carlos III Health Institute, Madrid, Spain.",
"Translational and Clinical Research Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Consejo Superior de Investigaciones Científicas (CSIC), and University of Salamanca, Salamanca, Spain.\nFlow Cytometry Service (NUCLEUS), University of Salamanca, Salamanca, Spain.\nInstitute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.\nDepartment of Medicine, University of Salamanca (Universidad de Salamanca), Salamanca, Spain.",
"Translational and Clinical Research Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Consejo Superior de Investigaciones Científicas (CSIC), and University of Salamanca, Salamanca, Spain.\nFlow Cytometry Service (NUCLEUS), University of Salamanca, Salamanca, Spain.\nInstitute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.\nDepartment of Medicine, University of Salamanca (Universidad de Salamanca), Salamanca, Spain.",
"Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.\nDepartment of Medicine, University of Salamanca (Universidad de Salamanca), Salamanca, Spain.\nBiomedical Research Networking Centre Consortium of Oncology (CIBERONC), Carlos III Health Institute, Madrid, Spain.\nDepartment of Hematology, University Hospital of Salamanca, Salamanca, Spain.",
"Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.\nDepartment of Medicine, University of Salamanca (Universidad de Salamanca), Salamanca, Spain.\nDepartment of Hematology, University Hospital of Salamanca, Salamanca, Spain.",
"Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.\nDepartment of Medicine, University of Salamanca (Universidad de Salamanca), Salamanca, Spain.\nBiomedical Research Networking Centre Consortium of Oncology (CIBERONC), Carlos III Health Institute, Madrid, Spain.\nDepartment of Hematology, University Hospital of Salamanca, Salamanca, Spain.",
"Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.\nDepartment of Medicine, University of Salamanca (Universidad de Salamanca), Salamanca, Spain.\nBiomedical Research Networking Centre Consortium of Oncology (CIBERONC), Carlos III Health Institute, Madrid, Spain.\nDepartment of Hematology, University Hospital of Salamanca, Salamanca, Spain.",
"Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.\nDepartment of Medicine, University of Salamanca (Universidad de Salamanca), Salamanca, Spain.\nBiomedical Research Networking Centre Consortium of Oncology (CIBERONC), Carlos III Health Institute, Madrid, Spain.\nDepartment of Hematology, University Hospital of Salamanca, Salamanca, Spain.",
"Department of Hematology, University Hospital of Salamanca, Salamanca, Spain.",
"Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.\nDepartment of Medicine, University of Salamanca (Universidad de Salamanca), Salamanca, Spain.\nBiomedical Research Networking Centre Consortium of Oncology (CIBERONC), Carlos III Health Institute, Madrid, Spain.\nDepartment of Hematology, University Hospital of Salamanca, Salamanca, Spain.",
"Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.\nDepartment of Medicine, University of Salamanca (Universidad de Salamanca), Salamanca, Spain.\nBiomedical Research Networking Centre Consortium of Oncology (CIBERONC), Carlos III Health Institute, Madrid, Spain.\nDepartment of Hematology, University Hospital of Salamanca, Salamanca, Spain.",
"Tettamanti Center and Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.",
null,
null,
"Translational and Clinical Research Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Consejo Superior de Investigaciones Científicas (CSIC), and University of Salamanca, Salamanca, Spain. [email protected].\nFlow Cytometry Service (NUCLEUS), University of Salamanca, Salamanca, Spain. [email protected].\nInstitute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain. [email protected].\nDepartment of Medicine, University of Salamanca (Universidad de Salamanca), Salamanca, Spain. [email protected].\nBiomedical Research Networking Centre Consortium of Oncology (CIBERONC), Carlos III Health Institute, Madrid, Spain. [email protected]."
] | [
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] | [] | 32.825714 | 7.648237 |
38759949 | 977 | The importance of a go-to-market strategy in the commercialisation of cellular immunotherapies. | Cellular immunotherapy (CIT) has both demonstrated outstanding levels of efficacy in cancer and presented unique commercialisation challenges. A historical analysis of go-to-market (G2M) strategies used to develop the first chimeric antigen receptor T cells (CAR-Ts) can offer insight into how companies leverage partnership or independence to ensure commercial success. Collaboration-based strategies, such as partnerships, acquisitions, and licensing deals, have predominated in the industry to maximise revenue and patient access. Manufacturing, logistical, and regulatory challenges have hindered independent commercialisation. Nonetheless, the industry is adapting to these challenges: novel technologies show superior affordability and implementability, and commercial solutions organisations (CSOs) increasingly help CIT companies navigate through commercialisation issues independently. G2M strategies in this industry are therefore likely to evolve, with independence becoming a feasible strategy for commercial success. | [
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] | 2024-05-18 | 1 | 38759949 | [
"G2M strategies",
"unique commercialisation challenges",
"CIT companies",
"commercial solutions organisations",
"regulatory challenges",
"commercial success",
"G2M",
"independent commercialisation",
"commercialisation issues",
"outstanding levels",
"companies",
"novel technologies",
"CIT",
"partnership",
"partnerships",
"superior affordability",
"licensing deals",
"independence",
"the first chimeric antigen receptor T cells",
"patient access",
"Cellular immunotherapy",
"Collaboration-based strategies",
"efficacy",
"cancer",
"market",
"first",
"implementability",
"insight",
"a feasible strategy",
"CSOs"
] | [] | 0 | 10.1016/j.drudis.2024.104028 | [
"Piñel-Neparidze",
"Bickerstaffe",
"Shah",
"Versnel"
] | [
"Cambridge Academy of Therapeutic Sciences (CATS), University of Cambridge, 17 Mill Lane, Cambridge CB2 1RX, UK. Electronic address: [email protected].",
"Syneos Health, 10 Bloomsbury Way, 4th Floor, London WC1A 2SL, UK.",
"Syneos Health, 10 Bloomsbury Way, 4th Floor, London WC1A 2SL, UK.",
"Cambridge Academy of Therapeutic Sciences (CATS), University of Cambridge, 17 Mill Lane, Cambridge CB2 1RX, UK."
] | [
"38759949"
] | [] | 9.052532 | 3.469001 |
38759487 | 978 | Acidity-targeting transition-aided universal chimeric antigen receptor T-cell (ATT-CAR-T) therapy for the treatment of solid tumors. | The use of CAR-T cells in treating solid tumors frequently faces significant challenges, mainly due to the heterogeneity of tumor antigens. This study assessed the efficacy of an acidity-targeting transition-aided universal chimeric antigen receptor T (ATT-CAR-T) cell strategy, which is facilitated by an acidity-targeted transition. Specifically, the EGFRvIII peptide was attached to the N-terminus of a pH-low insertion peptide. Triggered by the acidic conditions of the tumor microenvironment, this peptide alters its structure and selectively integrates into the membrane of solid tumor cells. The acidity-targeted transition component effectively relocated the EGFRvIII peptide across various tumor cell membranes; thus, allowing the direct destruction of these cells by EGFRvIII-specific CAR-T cells. This method was efficient even when endogenous antigens were absent. In vivo tests showed marked antigen modification within the acidic tumor microenvironment using this component. Integrating this component with CAR-T cell therapy showed high effectiveness in combating solid tumors. These results highlight the capability of ATT-CAR-T cell therapy to address the challenges presented by tumor heterogeneity and expand the utility of CAR-T cell therapy in the treatment of solid tumors. | [
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] | 2024-05-18 | 1 | 38759487 | [
"solid tumor cells",
"various tumor cell membranes",
"solid tumors",
"tumor antigens",
"tumor heterogeneity",
"CAR-T cell therapy",
"endogenous antigens",
"CAR-T cells",
"marked antigen modification",
"ATT-CAR-T cell therapy",
"the acidic tumor microenvironment",
"significant challenges",
"EGFRvIII-specific CAR-T cells",
"the tumor microenvironment",
"high effectiveness",
"ATT",
"an acidity-targeting transition-aided universal chimeric antigen receptor",
"vivo tests",
"The acidity-targeted transition component",
"these cells",
"T (ATT-CAR-T) cell strategy",
"an acidity-targeted transition",
"the EGFRvIII peptide",
"a pH-low insertion peptide",
"the acidic conditions",
"the direct destruction",
"this component",
"the membrane",
"the heterogeneity",
"the challenges"
] | [
"ATT-CAR-T",
"Acidic tumor microenvironment",
"CAR-T cells",
"Tumor immunotherapy",
"pHLIP"
] | 0 | 10.1016/j.biomaterials.2024.122607 | [
"Shi",
"Sun",
"Tuerhong",
"Li",
"Wang",
"Wang",
"Zheng",
"Zou",
"Lu",
"Sun",
"Zou",
"Shao",
"Du",
"Li",
"Liu",
"Meng"
] | [
"Department of Oncology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210008, China.",
"Department of Oncology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210008, China.",
"Department of Oncology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210008, China.",
"Department of Oncology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210008, China.",
"Department of Oncology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210008, China.",
"Department of Oncology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210008, China.",
"Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.",
"Department of Oncology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210008, China.",
"Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.",
"Department of Oncology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.",
"Department of Oncology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210008, China.",
"Department of Oncology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.",
"Department of Oncology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.",
"Department of Oncology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. Electronic address: [email protected].",
"Department of Oncology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. Electronic address: [email protected].",
"Department of Oncology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210008, China; Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. Electronic address: [email protected]."
] | [
"38759487"
] | [] | 9.553712 | 5.181929 |
38754916 | 979 | Safety and biological outcomes following a phase 1 trial of GD2-specific CAR-T cells in patients with GD2-positive metastatic melanoma and other solid cancers. | Chimeric antigen receptor (CAR) T cell therapies specific for the CD19 and B-cell maturation antigen have become an approved standard of care worldwide for relapsed and refractory B-cell malignancies. If CAR-T cell therapy for non-hematological malignancies is to achieve the same stage of clinical development, then iterative early-phase clinical testing can add value to the clinical development process for evaluating CAR-T cell products containing different CAR designs and manufactured under differing conditions.
We conducted a phase 1 trial of third-generation GD2-specific CAR-T cell therapy, which has previously been tested in neuroblastoma patients. In this study, the GD2-CAR-T therapy was evaluated for the first time in metastatic melanoma patients in combination with BRAF/MEK inhibitor therapy, and as a monotherapy in patients with colorectal cancer and a patient with fibromyxoid sarcoma. Feasibility and safety were determined and persistence studies, multiplex cytokine arrays on sera and detailed immune phenotyping of the original CAR-T products, the circulating CAR-T cells, and, in select patients, the tumor-infiltrating CAR-T cells were performed.
We demonstrate the feasibility of manufacturing CAR-T products at point of care for patients with solid cancer and show that a single intravenous infusion was well tolerated with no dose-limiting toxicities or severe adverse events. In addition, we note significant improvements in CAR-T cell immune phenotype, and expansion when a modified manufacturing procedure was adopted for the latter 6 patients recruited to this 12-patient trial. We also show evidence of CAR-T cell-mediated immune activity and in some patients expanded subsets of circulating myeloid cells after CAR-T cell therapy.
This is the first report of third-generation GD2-targeting CAR-T cells in patients with metastatic melanoma and other solid cancers such as colorectal cancer, showing feasibility, safety and immune activity, but limited clinical effect.
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"severe adverse events",
"Feasibility",
"feasibility",
"relapsed and refractory B-cell malignancies",
"iterative early-phase clinical testing",
"significant improvements"
] | [
"Chimeric antigen receptor - CAR",
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10.1158/1078-0432.CCR-18-1811 | [
"Gargett",
"Truong",
"Gardam",
"Yu",
"Ebert",
"Johnson",
"Yeo",
"Wittwer",
"Tapia Rico",
"Logan",
"Sivaloganathan",
"Collis",
"Ruszkiewicz",
"Brown"
] | [
"University of South Australia, Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology, Rundle Mall, South Australia, Australia [email protected].\nAdelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia.\nCancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia.",
"University of South Australia, Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology, Rundle Mall, South Australia, Australia.\nCancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia.",
"University of South Australia, Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology, Rundle Mall, South Australia, Australia.\nAdelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia.",
"University of South Australia, Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology, Rundle Mall, South Australia, Australia.\nCancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia.",
"University of South Australia, Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology, Rundle Mall, South Australia, Australia.\nAdelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia.\nCancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia.",
"Flinders University, Adelaide, South Australia, Australia.",
"University of South Australia, Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology, Rundle Mall, South Australia, Australia.",
"University of South Australia, Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology, Rundle Mall, South Australia, Australia.\nCancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia.",
"Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia.\nCancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia.",
"Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia.",
"Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia.",
"Surgical Pathology, SA Pathology, Adelaide, South Australia, Australia.",
"Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia.\nSurgical Pathology, SA Pathology, Adelaide, South Australia, Australia.\nSchool of Pharmacy and Medical Science, University of South Australia, Adelaide, South Australia, Australia.",
"University of South Australia, Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology, Rundle Mall, South Australia, Australia.\nAdelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia.\nCancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia."
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38754430 | 980 | Breast cancer-on-chip for patient-specific efficacy and safety testing of CAR-T cells. | Physiologically relevant human models that recapitulate the challenges of solid tumors and the tumor microenvironment (TME) are highly desired in the chimeric antigen receptor (CAR)-T cell field. We developed a breast cancer-on-chip model with an integrated endothelial barrier that enables the transmigration of perfused immune cells, their infiltration into the tumor, and concomitant monitoring of cytokine release during perfused culture over a period of up to 8 days. Here, we exemplified its use for investigating CAR-T cell efficacy and the ability to control the immune reaction with a pharmacological on/off switch. Additionally, we integrated primary breast cancer organoids to study patient-specific CAR-T cell efficacy. The modular architecture of our tumor-on-chip paves the way for studying the role of other cell types in the TME and thus provides the potential for broad application in bench-to-bedside translation as well as acceleration of the preclinical development of CAR-T cell products. | [
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"perfused immune cells",
"other cell types",
"solid tumors",
"primary breast cancer organoids",
"perfused culture",
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"an integrated endothelial barrier",
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"the chimeric antigen receptor",
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"our tumor",
"the tumor",
"the preclinical development",
"the TME",
"The modular architecture",
"the potential",
"the challenges",
"the transmigration"
] | [
"CAR-T cells",
"cancer",
"cancer immunotherapy",
"cancer model",
"organ-on-chip",
"solid tumor",
"tumor immunology",
"tumor microenvironment"
] | 0 | 10.1016/j.stem.2024.04.018 | [
"Maulana",
"Teufel",
"Cipriano",
"Roosz",
"Lazarevski",
"van den Hil",
"Scheller",
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] | [
"Department of Microphysiological Systems, Institute of Biomedical Engineering, Faculty of Medicine, Eberhard Karls University-Tübingen, 72074 Tübingen, Germany; NMI Natural and Medical Sciences Institute at the University of Tübingen, 72770 Reutlingen, Germany.",
"Department of Microphysiological Systems, Institute of Biomedical Engineering, Faculty of Medicine, Eberhard Karls University-Tübingen, 72074 Tübingen, Germany.",
"Department of Microphysiological Systems, Institute of Biomedical Engineering, Faculty of Medicine, Eberhard Karls University-Tübingen, 72074 Tübingen, Germany; 3R Center Tübingen for In Vitro Models and Alternatives to Animal Testing, 72074 Tübingen, Germany.",
"NMI Natural and Medical Sciences Institute at the University of Tübingen, 72770 Reutlingen, Germany.",
"Department of Microphysiological Systems, Institute of Biomedical Engineering, Faculty of Medicine, Eberhard Karls University-Tübingen, 72074 Tübingen, Germany.",
"Department of Anatomy and Embryology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.",
"Medizinische Klinik und Poliklinik II, Lehrstuhl für Zelluläre Immuntherapie, Universitätsklinikum Würzburg, 97078 Würzburg, Germany.",
"Department of Anatomy and Embryology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.",
"Department of Women's Health Tübingen, Eberhard Karls University-Tübingen, 72076 Tübingen, Germany.",
"Medizinische Klinik und Poliklinik II, Lehrstuhl für Zelluläre Immuntherapie, Universitätsklinikum Würzburg, 97078 Würzburg, Germany; Fraunhofer-Institut für Zelltherapie und Immunologie IZI, Außenstelle Würzburg Zelluläre Immuntherapie, 97082 Würzburg, Germany.",
"Medizinische Klinik und Poliklinik II, Lehrstuhl für Zelluläre Immuntherapie, Universitätsklinikum Würzburg, 97078 Würzburg, Germany. Electronic address: [email protected].",
"Department of Microphysiological Systems, Institute of Biomedical Engineering, Faculty of Medicine, Eberhard Karls University-Tübingen, 72074 Tübingen, Germany; NMI Natural and Medical Sciences Institute at the University of Tübingen, 72770 Reutlingen, Germany; 3R Center Tübingen for In Vitro Models and Alternatives to Animal Testing, 72074 Tübingen, Germany. Electronic address: [email protected]."
] | [
"38754430"
] | [] | 9.360162 | 5.222399 |
38754420 | 981 | CD37 is a safe chimeric antigen receptor target to treat acute myeloid leukemia. | Acute myeloid leukemia (AML) is characterized by the accumulation of immature myeloid cells in the bone marrow and the peripheral blood. Nearly half of the AML patients relapse after standard induction therapy, and new forms of therapy are urgently needed. Chimeric antigen receptor (CAR) T therapy has so far not been successful in AML due to lack of efficacy and safety. Indeed, the most attractive antigen targets are stem cell markers such as CD33 or CD123. We demonstrate that CD37, a mature B cell marker, is expressed in AML samples, and its presence correlates with the European LeukemiaNet (ELN) 2017 risk stratification. We repurpose the anti-lymphoma CD37CAR for the treatment of AML and show that CD37CAR T cells specifically kill AML cells, secrete proinflammatory cytokines, and control cancer progression in vivo. Importantly, CD37CAR T cells display no toxicity toward hematopoietic stem cells. Thus, CD37 is a promising and safe CAR T cell AML target. | [
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"hematopoietic stem cells",
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"a mature B cell marker",
"Acute myeloid leukemia",
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"a promising and safe CAR T cell AML target",
"cancer progression",
"new forms",
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"CD37",
"(AML",
"lack",
"efficacy",
"CD33",
"vivo",
"safety",
"CD123",
"the European LeukemiaNet",
"the bone marrow",
"the most attractive antigen targets",
"the peripheral blood"
] | [
"AML",
"CAR T cell",
"CD37",
"acute myeloid leukemia",
"chimeric antigen receptor",
"hematopoietic stem cell",
"immunotherapy",
"patient-derived xenograft"
] | 0 | 10.1016/j.xcrm.2024.101572
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10.1038/nbt.3235 | [
"Caulier",
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] | [
"Translational Research Unit, Section for Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway; Institute for Cancer Research, Department of Molecular Cell Biology, Oslo University Hospital, Oslo, Norway; Center for Cancer Cell Reprogramming (CanCell), Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.",
"Translational Research Unit, Section for Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway.",
"Department of Clinical Science, Precision Oncology Research Group, University of Bergen, 5021 Bergen, Norway; Centre for Cancer Biomarkers (CCBIO), University of Bergen, Bergen, Norway.",
"Department of Clinical Science, Precision Oncology Research Group, University of Bergen, 5021 Bergen, Norway; Centre for Pharmacy, Department of Clinical Science, University of Bergen, Bergen, Norway; Centre for Cancer Biomarkers (CCBIO), University of Bergen, Bergen, Norway.",
"Translational Research Unit, Section for Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway.",
"Institue of AI for Health, Helmholtz Munich, 85764 Neuherberg, Germany; School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.",
"Centre for Cancer Biomarkers (CCBIO), University of Bergen, Bergen, Norway; Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.",
"Translational Research Unit, Section for Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway.",
"Institute for Cancer Research, Department of Molecular Cell Biology, Oslo University Hospital, Oslo, Norway; Center for Cancer Cell Reprogramming (CanCell), Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.",
"Department of Clinical Science, Precision Oncology Research Group, University of Bergen, 5021 Bergen, Norway; Centre for Cancer Biomarkers (CCBIO), University of Bergen, Bergen, Norway.",
"Department of Clinical Science, Precision Oncology Research Group, University of Bergen, 5021 Bergen, Norway; Centre for Cancer Biomarkers (CCBIO), University of Bergen, Bergen, Norway.",
"Institute for Cancer Research, Department of Molecular Cell Biology, Oslo University Hospital, Oslo, Norway.",
"Translational Research Unit, Section for Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway.",
"Institue of AI for Health, Helmholtz Munich, 85764 Neuherberg, Germany.",
"Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany; German Center for Translational Cancer Research (DKTK), Partner Site Munich, Munich, Germany; Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, Research Center for Environmental Health (HMGU), Neuherberg, Germany.",
"Institute for Cancer Research, Department of Molecular Cell Biology, Oslo University Hospital, Oslo, Norway; Center for Cancer Cell Reprogramming (CanCell), Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Section for Biochemistry and Molecular Biology, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.",
"Centre for Cancer Biomarkers (CCBIO), University of Bergen, Bergen, Norway; Department of Medicine, Hematology Section, Haukeland University Hospital, Bergen, Norway.",
"Department of Clinical Science, Precision Oncology Research Group, University of Bergen, 5021 Bergen, Norway; Centre for Pharmacy, Department of Clinical Science, University of Bergen, Bergen, Norway; Centre for Cancer Biomarkers (CCBIO), University of Bergen, Bergen, Norway.",
"Translational Research Unit, Section for Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway.",
"Translational Research Unit, Section for Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway. Electronic address: [email protected]."
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38753658 | 982 | The antitumor effect of extracellular vesicles derived from cytokine-activated CD8+ T cells. | Extracellular vesicles (EVs) are nano-sized membrane particles secreted by various cell types that are involved in many important cellular processes. Recently, EVs originating from immune cells, such as dendritic cells, chimeric antigen receptor T cells, and natural killer cells, have attracted much attention because of their known direct and indirect antitumor activity. Here, we report the EVs released by cytokine-activated CD8+ T (caCD8) cells and its cytotoxicity against cancer cells. CaCD8 cells can release EVs following stimulation of CD8+ T cells with an anti-CD3 antibody and a cytokine cocktail ex vivo. The isolated vesicles have typical EV characteristics, such as an oval shape and a size distribution between 30 and 200 nm, as well as CD81 expression. Notably, caCD8-EVs displayed cytotoxicity against various cancer cells in vitro. Furthermore, mechanism analysis demonstrates that caCD8-EVs not only contain typical cytotoxic proteins (i.e. granzyme B and perforin), but also significantly enrich interferon γ (IFNγ) compared with caCD8 cells. EV-derived IFNγ participates in EV-induced apoptosis in cancer cells. Therefore, our data reveal antitumor effects of EVs secreted from caCD8 cells and the potential role of the EV-derived IFNγ. | [
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10.1038/s41419-019-1441-4 | [
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"Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China.\nKey Laboratory of Cancer Prevention and Therapy, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China.\nTianjin's Clinical Research Center for Cancer, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China.\nKey Laboratory of Cancer Immunology and Biotherapy, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China.\nDepartment of Immunology, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China.",
"Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China.\nKey Laboratory of Cancer Prevention and Therapy, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China.\nTianjin's Clinical Research Center for Cancer, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China.\nKey Laboratory of Cancer Immunology and Biotherapy, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China.\nDepartment of Immunology, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China.",
"Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China.\nKey Laboratory of Cancer Prevention and Therapy, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China.\nTianjin's Clinical Research Center for Cancer, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China.\nKey Laboratory of Cancer Immunology and Biotherapy, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China.\nDepartment of Immunology, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China.",
"Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China.\nKey Laboratory of Cancer Prevention and Therapy, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China.\nTianjin's Clinical Research Center for Cancer, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China.\nKey Laboratory of Cancer Immunology and Biotherapy, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China.\nDepartment of Immunology, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China.",
"Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China.\nKey Laboratory of Cancer Prevention and Therapy, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China.\nTianjin's Clinical Research Center for Cancer, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China.\nKey Laboratory of Cancer Immunology and Biotherapy, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China.\nDepartment of Immunology, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China.",
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38751430 | 983 | Charting new paradigms for CAR-T cell therapy beyond current Achilles heels. | Chimeric antigen receptor-T (CAR-T) cell therapy has made remarkable strides in treating hematological malignancies. However, the widespread adoption of CAR-T cell therapy is hindered by several challenges. These include concerns about the long-term and complex manufacturing process, as well as efficacy factors such as tumor antigen escape, CAR-T cell exhaustion, and the immunosuppressive tumor microenvironment. Additionally, safety issues like the risk of secondary cancers post-treatment, on-target off-tumor toxicity, and immune effector responses triggered by CAR-T cells are significant considerations. To address these obstacles, researchers have explored various strategies, including allogeneic universal CAR-T cell development, infusion of non-activated quiescent T cells within a 24-hour period, and | [
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10.1371/journal.pcbi.1009883 | [
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"Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.",
"Department of Health and Nursing, Nanfang College of Sun Yat-sen University, Guangzhou, China.",
"Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China.\nShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.\nUniversity of Chinese Academy of Sciences, Beijing, China.",
"Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China."
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10.1186/1471-2105-14-128 | [
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"Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.",
"Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.",
"Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.",
"Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.",
"Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.",
"Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.",
"British Columbia Cancer Agency, Vancouver, British Columbia, Canada.",
"Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.",
"Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.\nParker Institute for Cancer Immunotherapy, San Francisco, CA, USA.\nDepartment of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.",
"Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.\nPrincess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.",
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"Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.\nDepartment of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.",
"Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA.\nStanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.\nDepartment of Pathology, Stanford University School of Medicine, Stanford, CA, USA.\nLudwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA, USA.",
"Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.",
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"Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA.\nImmunology Graduate Program, Stanford University School of Medicine, Stanford, CA, USA.\nDepartment of Bioengineering, Stanford University, Stanford, CA, USA.\nDepartment of Chemical Engineering, Stanford University, Stanford, CA, USA.",
"Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. [email protected].\nParker Institute for Cancer Immunotherapy, San Francisco, CA, USA. [email protected].\nCancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA. [email protected].\nImmunology Graduate Program, Stanford University School of Medicine, Stanford, CA, USA. [email protected].\nDepartment of Medicine, Stanford University School of Medicine, Stanford, CA, USA. [email protected].\nStanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. [email protected].\nDepartment of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. [email protected].\nLudwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA, USA. [email protected]."
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38750245 | 985 | Identification of a clinically efficacious CAR T cell subset in diffuse large B cell lymphoma by dynamic multidimensional single-cell profiling. | Chimeric antigen receptor (CAR) T cells used for the treatment of B cell malignancies can identify T cell subsets with superior clinical activity. Here, using infusion products of individuals with large B cell lymphoma, we integrated functional profiling using timelapse imaging microscopy in nanowell grids with subcellular profiling and single-cell RNA sequencing to identify a signature of multifunctional CD8 | [
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] | 2024-05-16 | 60 | 38750245 | [
"T cell subsets",
"large B cell lymphoma",
"B cell malignancies",
"subcellular profiling",
"functional profiling",
"timelapse imaging microscopy",
"Chimeric antigen receptor",
"superior clinical activity",
"nanowell grids",
"CAR) T cells",
"infusion products",
"single-cell RNA",
"multifunctional CD8",
"CAR",
"RNA",
"individuals",
"a signature",
"the treatment",
"we"
] | [] | 0 | 10.1038/s43018-024-00768-3 | [
"Rezvan",
"Romain",
"Fathi",
"Heeke",
"Martinez-Paniagua",
"An",
"Bandey",
"Montalvo",
"Adolacion",
"Saeedi",
"Sadeghi",
"Fousek",
"Puebla-Osorio",
"Cooper",
"Bernatchez",
"Singh",
"Ahmed",
"Mattie",
"Bot",
"Neelapu",
"Varadarajan"
] | [
"Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX, USA.",
"Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX, USA.",
"CellChorus, Houston, TX, USA.",
"Kite, a Gilead Company, Santa Monica, CA, USA.",
"Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX, USA.",
"Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX, USA.",
"Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX, USA.",
"Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX, USA.",
"Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX, USA.",
"Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX, USA.",
"Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX, USA.",
"Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.",
"Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.",
"CellChorus, Houston, TX, USA.",
"Department of Biologics Development, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.",
"Divsion of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.",
"Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.",
"Kite, a Gilead Company, Santa Monica, CA, USA.",
"Kite, a Gilead Company, Santa Monica, CA, USA.",
"Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.",
"Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX, USA. [email protected]."
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38750075 | 986 | GPC3-targeted CAR-T cells expressing GLUT1 or AGK exhibit enhanced antitumor activity against hepatocellular carcinoma. | Chimeric antigen receptor-expressing T (CAR-T) cells induce robust antitumor responses in patients with hematologic malignancies. However, CAR-T cells exhibit only limited efficacy against solid tumors such as hepatocellular carcinoma (HCC), partially due to their limited expansion and persistence. CD8 | [
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10.1182/blood.2018885863 | [
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] | [
"State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China.\nDepartment of Laboratory Medicine, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China.",
"State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China.",
"State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China.",
"State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China.",
"State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China.\nCARsgen Therapeutics, Shanghai, 200032, China.",
"State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China.\nCARsgen Therapeutics, Shanghai, 200032, China.",
"State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China. [email protected].\nCARsgen Therapeutics, Shanghai, 200032, China. [email protected].",
"State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China. [email protected].\nCARsgen Therapeutics, Shanghai, 200032, China. [email protected]."
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38747974 | 987 | Arming Vδ2 T Cells with Chimeric Antigen Receptors to Combat Cancer. | Immunotherapy has emerged as a promising approach in the field of cancer treatment, with chimeric antigen receptor (CAR) T-cell therapy demonstrating remarkable success. However, challenges such as tumor antigen heterogeneity, immune evasion, and the limited persistence of CAR-T cells have prompted the exploration of alternative cell types for CAR-based strategies. Gamma delta T cells, a unique subset of lymphocytes with inherent tumor recognition capabilities and versatile immune functions, have garnered increasing attention in recent years. In this review, we present how arming Vδ2-T cells might be the basis for next-generation immunotherapies against solid tumors. Following a comprehensive overview of γδ T-cell biology and innovative CAR engineering strategies, we discuss the clinical potential of Vδ2 CAR-T cells in overcoming the current limitations of immunotherapy in solid tumors. Although the applications of Vδ2 CAR-T cells in cancer research are relatively in their infancy and many challenges are yet to be identified, Vδ2 CAR-T cells represent a promising breakthrough in cancer immunotherapy. | [
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"a promising breakthrough"
] | [] | 0 | 10.1158/1078-0432.CCR-23-3495 | [
"Thomas",
"Paris",
"Pecqueur"
] | [
"Nantes Université, CRCI2NA, INSERM, CNRS, Nantes, France.",
"Nantes Université, CRCI2NA, INSERM, CNRS, Nantes, France.",
"Nantes Université, CRCI2NA, INSERM, CNRS, Nantes, France."
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38747505 | 988 | Long-term Remissions Following CD20-Directed Chimeric Antigen Receptor-Adoptive T-cell Therapy. | Chimeric antigen receptor (CAR) T-cell therapy produces high response rates in refractory B-cell non-Hodgkin lymphoma, but long-term data are minimal to date. In this study, we present long-term follow-up of a pilot trial testing a CD20-targeting third-generation CAR in patients with relapsed B-cell lymphomas following cyclophosphamide-only lymphodepletion. Two of the three patients in the trial, with mantle cell lymphoma and follicular lymphoma, had remissions lasting more than 7 years, though they ultimately relapsed. The absence of B-cell aplasia in both patients suggested a lack of functional CAR T-cell persistence, leading to the hypothesis that endogenous immune responses were responsible for these long-term remissions. Correlative immunologic analyses supported this hypothesis, with evidence of new humoral and cellular antitumor immune responses proximal to clinical response time points. Collectively, our results suggest that CAR T-cell therapy may facilitate epitope spreading and endogenous immune response formation in lymphomas. Significance: Two of three patients treated with CD20-targeted CAR T-cell therapy had long-term remissions, with evidence of endogenous antitumor immune response formation. Further investigation is warranted to develop conditions that promote epitope spreading in lymphomas. | [
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] | 2024-05-15 | 23 | 38747505 | [
"endogenous immune responses",
"mantle cell lymphoma",
"endogenous antitumor immune response formation",
"high response rates",
"clinical response time points",
"CAR T-cell therapy",
"functional CAR T-cell persistence",
"refractory B-cell non-Hodgkin lymphoma",
"follicular lymphoma",
"CD20-targeted CAR T-cell therapy",
"new humoral and cellular antitumor immune responses",
"relapsed B-cell lymphomas",
"lymphomas",
"patients",
"B-cell aplasia",
"CAR) T-cell therapy",
"long-term remissions",
"non-Hodgkin",
"remissions",
"Correlative immunologic analyses",
"long-term data",
"evidence",
"epitope",
"Chimeric antigen receptor",
"Further investigation",
"conditions",
"long-term follow-up",
"these long-term remissions",
"CAR",
"third"
] | [] | 0 | 10.1158/2643-3230.BCD-23-0263 | [
"Mo",
"Lee",
"Coffey",
"Voillet",
"Kirsch",
"Gottardo",
"Smythe",
"Yeung",
"Greenbaum",
"Green",
"Maloney",
"Till"
] | [
"Department of Medicine, University of Washington, Seattle, Washington.",
"Fred Hutchinson Cancer Center, Translational Science and Therapeutics Division, Seattle, Washington.",
"Department of Medicine, University of Washington, Seattle, Washington.\nUniversity of Miami, Miami, Florida.",
"Fred Hutchinson Cancer Center, Vaccine and Infectious Disease Division, Seattle, Washington.\nCape Town HVTN Immunology Laboratory, Hutchinson Centre Research Institute of South Africa, Cape Town, South Africa.",
"Adaptive Biotechnologies, Seattle, Washington.",
"Fred Hutchinson Cancer Center, Vaccine and Infectious Disease Division, Seattle, Washington.\nUniversity of Lausanne and Lausanne University Hospital, Lausanne, Switzerland.",
"Fred Hutchinson Cancer Center, Translational Science and Therapeutics Division, Seattle, Washington.",
"Fred Hutchinson Cancer Center, Translational Science and Therapeutics Division, Seattle, Washington.\nDepartment of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington.",
"Fred Hutchinson Cancer Center, Translational Science and Therapeutics Division, Seattle, Washington.",
"Department of Medicine, University of Washington, Seattle, Washington.\nFred Hutchinson Cancer Center, Translational Science and Therapeutics Division, Seattle, Washington.",
"Department of Medicine, University of Washington, Seattle, Washington.\nFred Hutchinson Cancer Center, Translational Science and Therapeutics Division, Seattle, Washington.",
"Department of Medicine, University of Washington, Seattle, Washington.\nFred Hutchinson Cancer Center, Translational Science and Therapeutics Division, Seattle, Washington."
] | [
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] | [] | 6.627985 | 5.14581 |
38747501 | 989 | Genotoxicity Associated with Retroviral CAR Transduction of ATM-Deficient T Cells. | Somatic variants in DNA damage response genes such as ATM are widespread in hematologic malignancies. ATM protein is essential for double-strand DNA break repair. Germline ATM deficiencies underlie ataxia-telangiectasia (A-T), a disease manifested by radiosensitivity, immunodeficiency, and predisposition to lymphoid malignancies. Patients with A-T diagnosed with malignancies have poor tolerance to chemotherapy or radiation. In this study, we investigated chimeric antigen receptor (CAR) T cells using primary T cells from patients with A-T (ATM-/-), heterozygote donors (ATM+/-), and healthy donors. ATM-/- T cells proliferate and can be successfully transduced with CARs, though functional impairment of ATM-/- CAR T-cells was observed. Retroviral transduction of the CAR in ATM-/- T cells resulted in high rates of chromosomal lesions at CAR insertion sites, as confirmed by next-generation long-read sequencing. This work suggests that ATM is essential to preserve genome integrity of CAR T-cells during retroviral manufacturing, and its lack poses a risk of chromosomal translocations and potential leukemogenicity. Significance: CAR T-cells are clinically approved genetically modified cells, but the control of genome integrity remains largely uncharacterized. This study demonstrates that ATM deficiency marginally impairs CAR T-cell function and results in high rates of chromosomal aberrations after retroviral transduction, which may be of concern in patients with DNA repair deficiencies. | [
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] | 2024-05-15 | 25 | 38747501 | [
"ATM-/- T cells",
"primary T cells",
"ATM deficiency",
"Germline ATM deficiencies",
"ATM protein",
"DNA repair deficiencies",
"CAR",
"ATM",
"ATM-/- CAR T-cells",
"CAR T-cells",
"CAR) T cells",
"CAR insertion sites",
"DNA damage response genes",
"chromosomal lesions",
"chromosomal translocations",
"chromosomal aberrations",
"CAR T-cell function",
"Retroviral transduction",
"retroviral transduction",
"genome integrity",
"high rates",
"retroviral manufacturing",
"lymphoid malignancies",
"hematologic malignancies",
"ATM-/-",
"CARs",
"chimeric antigen receptor",
"malignancies",
"poor tolerance",
"Patients"
] | [] | 0 | 10.1158/2643-3230.BCD-23-0268 | [
"Rozenbaum",
"Fluss",
"Marcu-Malina",
"Sarouk",
"Meir",
"Elitzur",
"Zinger",
"Jacob-Hirsch",
"Saar",
"Rechavi",
"Jacoby"
] | [
"Cell Therapy Lab, Sheba Medical Center, Tel Hashomer, Israel.",
"Cancer Research Center, Sheba Medical Center, Tel Hashomer, Israel.\nWohl Centre for Translational Medicine, Sheba Medical Center, Tel Hashomer, Israel.",
"Hematology Laboratory, Sheba Medical Center, Tel Hashomer, Israel.",
"National A-T Center, Pediatric Pulmonology Unit, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel.",
"Cell Therapy Lab, Sheba Medical Center, Tel Hashomer, Israel.",
"Department of Pediatric Hematology-Oncology, Schneider Children's Medical Center, Petah Tikva, Israel.\nFaculty of Medicinal & Health Sciences, Tel Aviv University, Tel Aviv, Israel.",
"Cancer Research Center, Sheba Medical Center, Tel Hashomer, Israel.",
"Cancer Research Center, Sheba Medical Center, Tel Hashomer, Israel.\nWohl Centre for Translational Medicine, Sheba Medical Center, Tel Hashomer, Israel.",
"Cancer Research Center, Sheba Medical Center, Tel Hashomer, Israel.\nWohl Centre for Translational Medicine, Sheba Medical Center, Tel Hashomer, Israel.",
"Cancer Research Center, Sheba Medical Center, Tel Hashomer, Israel.\nWohl Centre for Translational Medicine, Sheba Medical Center, Tel Hashomer, Israel.\nFaculty of Medicinal & Health Sciences, Tel Aviv University, Tel Aviv, Israel.",
"Cell Therapy Lab, Sheba Medical Center, Tel Hashomer, Israel.\nFaculty of Medicinal & Health Sciences, Tel Aviv University, Tel Aviv, Israel.\nDivision of Pediatric Hematology and Oncology, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel."
] | [
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] | [] | 7.179661 | 7.003933 |
38746996 | 990 | CAR T Cell Membrane Camouflaged Nanocatalyst Augments CAR T Cell Therapy Efficacy Against Solid Tumor. | The immunosuppressive tumor microenvironment (TME) reduces the chimeric antigen receptor (CAR) T-cell therapy against solid tumors. Here, a CAR T cell membrane-camouflaged nanocatalyst (ACSP@TCM) is prepared to augment CAR T cell therapy efficacy against solid tumors. ACSP@TCM is prepared by encapsulating core/shell Au/Cu | [
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] | 2024-05-15 | 1 | 38746996 | [
"CAR T cell therapy efficacy",
"solid tumors",
"a CAR T cell membrane-camouflaged nanocatalyst",
"TME",
"ACSP@TCM",
"CAR) T-cell therapy",
"the chimeric antigen receptor",
"The immunosuppressive tumor microenvironment",
"core/shell Au/Cu",
"Au/Cu"
] | [
"CAR T cell therapy",
"cell membrane coating technique",
"chemodynamic therapy",
"photothermal therapy",
"solid tumors"
] | 0 | 10.1002/smll.202401299 | [
"Wu",
"Li",
"Chen",
"Hu",
"Wang",
"She",
"Huang",
"Liu",
"Jiang"
] | [
"College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, P. R. China.",
"Department of Orthopedics Trauma and Microsurgery, School of Pharmaceutical Sciences, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, P. R. China.",
"College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, P. R. China.",
"Department of Orthopedics Trauma and Microsurgery, School of Pharmaceutical Sciences, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, P. R. China.",
"College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, P. R. China.",
"College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, P. R. China.",
"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, 300020, P. R. China.\nTianjin Institutes of Health Science, Tianjin, 301600, P. R. China.",
"College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, P. R. China.\nSchool of Chemical and Environmental Engineering, Wuhan Polytechnic University, Wuhan, 430023, P. R. China.\nHubei Key Laboratory of Radiation Chemistry and Functional Materials School of Nuclear Technology and Chemistry and Biology, Hubei University of Science and Technology, Xianning, 437100, China.",
"Department of Orthopedics Trauma and Microsurgery, School of Pharmaceutical Sciences, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, P. R. China.\nKey Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE), Wuhan University, Wuhan, 430071, P. R. China."
] | [
"38746996"
] | [] | 9.820909 | 4.727765 |
38746248 | 991 | Sensitive bispecific chimeric T cell receptors for cancer therapy. | The expression of a synthetic chimeric antigen receptor (CAR) to redirect antigen specificity of T cells is transforming the treatment of hematological malignancies and autoimmune diseases [1-7]. In cancer, durable efficacy is frequently limited by the escape of tumors that express low levels or lack the target antigen [8-12]. These clinical results emphasize the need for immune receptors that combine high sensitivity and multispecificity to improve outcomes. Current mono- and bispecific CARs do not faithfully recapitulate T cell receptor (TCR) function and require high antigen levels on tumor cells for recognition [13-17]. Here, we describe a novel synthetic chimeric TCR (ChTCR) that exhibits superior antigen sensitivity and is readily adapted for bispecific targeting. Bispecific ChTCRs mimic TCR structure, form classical immune synapses, and exhibit TCR-like proximal signaling. T cells expressing Bi-ChTCRs more effectively eliminated tumors with heterogeneous antigen expression in vivo compared to T cells expressing optimized bispecific CARs. The Bi-ChTCR architecture is resilient and can be designed to target multiple B cell lineage and multiple myeloma antigens. Our findings identify a broadly applicable approach for engineering T cells to target hematologic malignancies with heterogeneous antigen expression, thereby overcoming the most frequent mechanism of relapse after current CAR T therapies. | [
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] | [] | 0 | 10.21203/rs.3.rs-4253777/v1 | [
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] | [
"Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.",
"Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.\nDepartment of Immunology, University of Washington, Seattle, WA 98195, USA.",
"Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.",
"Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.",
"Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.",
"Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.",
"Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.",
"Department of Cell Biology, Yale School of Medicine, New Haven, CT 06520, USA.\nYale Cancer Center, Yale University, New Haven, CT 06520, USA.",
"Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.\nDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.",
"Seattle Children's Research Institute, Ben Towne Center For Childhood Cancer Research, Seattle, WA 98105, USA.",
"Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.",
"Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.",
"Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.",
"Seattle Children's Research Institute, Ben Towne Center For Childhood Cancer Research, Seattle, WA 98105, USA.",
"Department of Cell Biology, Yale School of Medicine, New Haven, CT 06520, USA.\nYale Cancer Center, Yale University, New Haven, CT 06520, USA.",
"Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.\nDepartment of Medicine, University of Washington, Seattle, WA 98195, USA."
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38745768 | 992 | Tri-specific killer engager: unleashing multi-synergic power against cancer. | Cancer continues to be a global health concern, necessitating innovative solutions for treatment. Tri-specific killer engagers (TriKEs) have emerged as a promising class of immunotherapeutic agents, offering a multifaceted approach to cancer treatment. TriKEs simultaneously engage and activate natural killer (NK) cells while specifically targeting cancer cells, representing an outstanding advancement in immunotherapy. This review explores the generation and mechanisms of TriKEs, highlighting their advantages over other immunotherapies and discussing their potential impact on clinical trials and cancer treatment. TriKEs are composed of three distinct domains, primarily antibody-derived building blocks, linked together by short amino acid sequences. They incorporate critical elements, anti-cluster of differentiation 16 (CD16) and interleukin-15 (IL-15), which activate and enhance NK cell function, together with specific antibody to target each cancer. TriKEs exhibit remarkable potential in preclinical and early clinical studies across various cancer types, making them a versatile tool in cancer immunotherapy. Comparative analyses with other immunotherapies, such as chimeric antigen receptor-T (CAR-T) cell therapy, immune checkpoint inhibitors (ICIs), cytokine therapies, and monoclonal antibodies (mAbs), reveal the unique advantages of TriKEs. They offer a safer pathway for immunotherapy by targeting cancer cells without hyperactivating T cells, reducing off-target effects and complications. The future of TriKEs involves addressing challenges related to dosing, tumor-associated antigen (TAA) expression, and NK cell suppression. Researchers are exploring innovative dosing strategies, enhancing specificity through tumor-specific antigens (TSAs), and combining TriKEs with other therapies for increased efficacy. | [
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10.1136/jitc-2021-002980 | [
"Winidmanokul",
"Panya",
"Okada"
] | [
"Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand.\nDivision of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto 860-0811, Japan.",
"Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand.\nCell Engineering for Cancer Therapy Research Group, Chiang Mai University, Chiang Mai 50200, Thailand.",
"Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto 860-0811, Japan."
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38745670 | 993 | Case report: Preventive infusion of donor-derived CD7 chimeric antigen receptor T cells after allogeneic hematopoietic stem cell transplantation. | Chimeric antigen receptor T cells (CAR T) targeting CD7 for T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) showed promising efficacy and safety in some clinical trials. However, most of them were bridged with allogeneic hematopoietic stem cell transplantation (allo-HSCT). We described successful treatment with preventive donor-derived anti-CD7 CAR-T therapy in a case of refractory T lymphoblastic lymphoma following allo-HSCT, who could not receive autologous anti-CD7 CAR-T products due to the low-quality of T lymphocytes. To date, the patient's complete remission has persisted for 20 months after HSCT. | [
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"CD7 CAR-T",
"HSCT",
"T-ALL/LBL",
"complete remission",
"preventive infusion"
] | 0 | 10.3389/fimmu.2024.1381308
10.1016/j.omto.2022.02.013
10.1016/j.jtct.2022.11.013
10.1182/hematology.2020000134
10.1007/s11899-019-00501-3
10.1182/blood.2022016595
10.1186/s40364-022-00352-w
10.1186/s13045-023-01427-3
10.1200/JCO.21.00389
10.1002/ajh.25957
10.1182/blood-2012-07-444372
10.1002/ajh.26160
10.1186/s13045-021-01092-4
10.1182/blood.2021014498 | [
"Jiang",
"Feng",
"Zhu",
"Wei",
"Zhao",
"Liu",
"Shao",
"Wang"
] | [
"Department of Hematology, Shanghai Zhaxin Traditional Chinese and Western Medicine Hospital, Shanghai, China.",
"Department of Hematology, Shanghai Zhaxin Traditional Chinese and Western Medicine Hospital, Shanghai, China.",
"Department of Hematology, Shanghai Zhaxin Traditional Chinese and Western Medicine Hospital, Shanghai, China.",
"Department of Hematology, Shanghai Zhaxin Traditional Chinese and Western Medicine Hospital, Shanghai, China.",
"Department of Hematology, Shanghai Zhaxin Traditional Chinese and Western Medicine Hospital, Shanghai, China.",
"Department of Hematology, Shanghai Zhaxin Traditional Chinese and Western Medicine Hospital, Shanghai, China.",
"Department of Hematology, Shanghai Zhaxin Traditional Chinese and Western Medicine Hospital, Shanghai, China.",
"Department of Hematology, Shanghai Zhaxin Traditional Chinese and Western Medicine Hospital, Shanghai, China."
] | [
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"23100309",
"33725422",
"34034795",
"35500125"
] | [] | 6.514888 | 5.905207 |
38745479 | 994 | Correction: Chimeric Antigen Receptor T Cells Targeting CD79b Show Efficacy in Lymphoma with or without Cotargeting CD19. | null | [
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] | 2024-05-15 | 1 | 38745479 | [] | [] | 0 | 10.1158/1078-0432.CCR-24-1059 | [
"Ormhøj",
"Scarfò",
"Cabral",
"Bailey",
"Lorrey",
"Bouffard",
"Castano",
"Larson",
"Riley",
"Schmidts",
"Choi",
"Andersen",
"Cédile",
"Nyvold",
"Christensen",
"Gjerstorff",
"Ditzel",
"Weinstock",
"Barington",
"Frigault",
"Maus"
] | [
null,
null,
null,
null,
null,
null,
null,
null,
null,
null,
null,
null,
null,
null,
null,
null,
null,
null,
null,
null,
null
] | [
"38745479"
] | [] | 32.866657 | 7.396087 |
38745414 | 995 | Granzyme B-activated IL18 potentiates αβ and γδ CAR T cell immunotherapy in a tumor-dependent manner. | Interleukin (IL)18 is a potent pro-inflammatory cytokine that is activated upon caspase 1 cleavage of the latent precursor, pro-IL18. Therapeutic T cell armoring with IL18 promotes autocrine stimulation and positive modulation of the tumor microenvironment (TME). However, existing strategies are imperfect since they involve constitutive/poorly regulated activity or fail to modify the TME. Here, we have substituted the caspase 1 cleavage site within pro-IL18 with that preferred by granzyme B, yielding GzB-IL18. We demonstrate that GzB-IL18 is constitutively released but remains functionally latent unless chimeric antigen receptor (CAR) T cells are activated, owing to concomitant granzyme B release. Armoring with GzB-IL18 enhances cytolytic activity, proliferation, interferon (IFN)-γ release, and anti-tumor efficacy by a similar magnitude to constitutively active IL18. We also demonstrate that GzB-IL18 provides a highly effective armoring strategy for γδ CAR T cells, leading to enhanced metabolic fitness and significant potentiation of therapeutic activity. Finally, we show that constitutively active IL18 can unmask CAR T cell-mediated cytokine release syndrome in immunocompetent mice. By contrast, GzB-IL18 promotes anti-tumor activity and myeloid cell re-programming without inducing such toxicity. Using this stringent system, we have tightly coupled the biological activity of IL18 to the activation state of the host CAR T cell, favoring safer clinical implementation of this technology. | [
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"the biological activity",
"TME",
"-",
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] | [
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"Hull",
"Larcombe-Young",
"Mazza",
"George",
"Davies",
"Schurich",
"Maher"
] | [
"Leucid Bio Ltd, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.",
"King's College London, School of Cancer and Pharmaceutical Sciences, CAR Mechanics Lab, Guy's Cancer Centre, Great Maze Pond, London SE1 9RT, UK.",
"Leucid Bio Ltd, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.",
"King's College London, Department of Infectious Diseases, School of Immunology and Microbial Sciences, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.",
"Leucid Bio Ltd, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.",
"King's College London, Department of Infectious Diseases, School of Immunology and Microbial Sciences, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.",
"Leucid Bio Ltd, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK; King's College London, School of Cancer and Pharmaceutical Sciences, CAR Mechanics Lab, Guy's Cancer Centre, Great Maze Pond, London SE1 9RT, UK; Department of Immunology, Eastbourne Hospital, Kings Drive, Eastbourne, East Sussex BN21 2UD, UK. Electronic address: [email protected]."
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38745250 | 996 | CAR T cells outperform CAR NK cells in CAR-mediated effector functions in head-to-head comparison. | CAR NK cells as vehicles for engineered "off-the-shelf" cellular cancer immunotherapy have attracted significant interest. Nonetheless, a comprehensive comparative assessment of the anticancer activity of CAR T cells and CAR NK cells carrying approved benchmark anti-CD19 CAR constructs is missing. Here, we report a direct head-to-head comparison of CD19-directed human T and NK cells.
We generated CAR T and CAR NK cells derived from healthy donor PBMC by retroviral transduction with the same benchmark second-generation anti-CD19 CAR construct, FMC63.28z. We investigated IFN-γ secretion and direct cytotoxicity in vitro against various CD19
Our main findings are a drastically reduced capacity for CAR-mediated IFN-γ production and lower CAR-mediated cytotoxicity of CAR NK cells relative to CAR T cells in vitro. Consistent with these in vitro findings, we report superior anticancer activity of autologous CAR T cells compared with allogeneic CAR NK cells in vivo.
CAR T cells had significantly higher CAR-mediated effector functions than CAR NK cells in vitro against several cancer cell lines and autologous CAR T cells outperformed allogeneic CAR NK cells both in vitro and in vivo. CAR NK cells will likely benefit from further engineering to enhance anticancer activity to ultimately fulfill the promise of an effective off-the-shelf product. | [
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10.1182/blood-2015-06-654780
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10.1016/j.cell.2023.06.002 | [
"Egli",
"Kaulfuss",
"Mietz",
"Picozzi",
"Verhoeyen",
"Münz",
"Chijioke"
] | [
"Cellular Immunotherapy, Institute of Experimental Immunology, University of Zürich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.",
"Cellular Immunotherapy, Institute of Experimental Immunology, University of Zürich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.",
"Cellular Immunotherapy, Institute of Experimental Immunology, University of Zürich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.",
"Cellular Immunotherapy, Institute of Experimental Immunology, University of Zürich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.",
"International Center for Infectiology, research team Enveloped Viruses, Vectors and Innate Responses, Institut national de la Santé et de la recherche médicale, unité 1111, Unité mixte de recherche 5308, Centre national de la recherche scientifique, École Normale Supérieure de Lyon, Université Claude Bernard Lyon 1, University of Lyon, Lyon, France.\nUniversité Côte d'Azur, Institut National de La Santé Et de La Recherche Médicale, Centre Méditerranéen de Médecine Moléculaire, Nice, France.",
"Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zurich, Switzerland.",
"Cellular Immunotherapy, Institute of Experimental Immunology, University of Zürich, Winterthurerstrasse 190, 8057, Zurich, Switzerland. [email protected].\nInstitute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland. [email protected]."
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] | 2024-05-15 | 3 | 38745000 | [] | [] | 0 | 10.1038/s41582-024-00972-w
10.1056/NEJMoa2314390
10.1038/s41591-024-02893-z | [
"Fyfe"
] | [
"Nature Reviews Neurology, . [email protected]."
] | [
"38745000",
"38477966",
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38744947 | 998 | Generation of allogeneic CAR-NKT cells from hematopoietic stem and progenitor cells using a clinically guided culture method. | Cancer immunotherapy with autologous chimeric antigen receptor (CAR) T cells faces challenges in manufacturing and patient selection that could be avoided by using 'off-the-shelf' products, such as allogeneic CAR natural killer T ( | [
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] | [] | 0 | 10.1038/s41587-024-02226-y
10.1038/s41591-023-02363-y
10.1016/j.stem.2023.02.009
10.1016/j.trecan.2021.08.004 | [
"Li",
"Zhou",
"Yu",
"Kim",
"Li",
"Lee",
"Zhou",
"Chen",
"Zhu",
"Wang",
"Li",
"Yu",
"Dunn",
"Guo",
"Cen",
"Husman",
"Bajpai",
"Kramer",
"Wilson",
"Fang",
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"Li",
"Zhou",
"Zhang",
"Hahn",
"Zhu",
"Ma",
"Pan",
"Lusis",
"Zhou",
"Seet",
"Kohn",
"Wang",
"Zhou",
"Pellegrini",
"Puliafito",
"Larson",
"Yang"
] | [
"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Medicine, Division of Cardiology, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.",
"Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, USA.",
"Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.",
"Department of Medicine, Division of Cardiology, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.\nDepartment of Medicine, Division of Cardiology, University of California, Los Angeles, Los Angeles, CA, USA.\nHuman Genetics, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA.",
"Eli and Edythe Broad Centre of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA.\nJonsson Comprehensive Cancer Centre, University of California, Los Angeles, Los Angeles, CA, USA.\nDepartment of Medicine, Division of Hematology/Oncology, University of California, Los Angeles, Los Angeles, CA, USA.\nMolecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.\nEli and Edythe Broad Centre of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA.\nDepartment of Pediatrics, Division of Hematology/Oncology, University of California, Los Angeles, Los Angeles, CA, USA.",
"Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, USA.",
"Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA.",
"Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA.\nInstitute for Quantitative and Computational Biosciences-The Collaboratory, University of California, Los Angeles, Los Angeles, CA, USA.\nDepartment of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Hematology and Oncology, University of California, Los Angeles, Los Angeles, CA, USA.",
"Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, Los Angeles, CA, USA.\nDepartment of Internal Medicine, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA. [email protected].\nEli and Edythe Broad Centre of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA. [email protected].\nJonsson Comprehensive Cancer Centre, University of California, Los Angeles, Los Angeles, CA, USA. [email protected].\nMolecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA. [email protected]."
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] | [] | 8.236028 | 3.313617 |
38743236 | 999 | Generation of Anti-HIV CAR-T Cells for Preclinical Research. | The inability of people living with HIV (PLWH) to eradicate human immunodeficiency virus (HIV) infection is due in part to the inadequate HIV-specific cellular immune response. The antiviral function of cytotoxic CD8+ T cells, which are crucial for HIV control, is impaired during chronic viral infection because of viral escape mutations, immune exhaustion, HIV antigen downregulation, inflammation, and apoptosis. In addition, some HIV-infected cells either localize to tissue sanctuaries inaccessible to CD8+ T cells or are intrinsically resistant to CD8+ T cell killing. The novel design of synthetic chimeric antigen receptors (CARs) that enable T cells to target specific antigens has led to the development of potent and effective CAR-T cell therapies. While initial clinical trials using anti-HIV CAR-T cells performed over 20 years ago showed limited anti-HIV effects, the improved CAR-T cell design, which enabled its success in treating cancer, has reinstated CAR-T cell therapy as a strategy for HIV cure with notable progress being made in the recent decade.Effective CAR-T cell therapy against HIV infection requires the generation of anti-HIV CAR-T cells with potent in vivo activity against HIV-infected cells. Preclinical evaluation of anti-HIV efficacy of CAR-T cells and their safety is fundamental for supporting the initiation of subsequent clinical trials in PLWH. For these preclinical studies, we developed a novel humanized mouse model supporting in vivo HIV infection, the development of viremia, and the evaluation of novel HIV therapeutics. Preclinical assessment of anti-HIV CAR-T cells using this mouse model involves a multistep process including peripheral blood mononuclear cells (PBMCs) harvested from human donors, T cell purification, ex vivo T cell activation, transduction with lentiviral vectors encoding an anti-HIV CAR, CAR-T cell expansion and infusion in mice intrasplenically injected with autologous PBMCs followed by the determination of CAR-T cell capacity for HIV suppression. Each of the steps described in the following protocol were optimized in the lab to maximize the quantity and quality of the final anti-HIV CAR-T cell products. | [
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"specific antigens",
"an anti-HIV CAR",
"synthetic chimeric antigen receptors",
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] | [
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] | 0 | 10.1007/978-1-0716-3862-0_20
10.1016/S2352-3018(17)30183-2
10.1038/8394
10.1172/JCI134815
10.1111/imr.12823
10.1016/j.ccell.2020.07.005
10.1038/s41591-020-1039-5
10.3389/fimmu.2022.873701
10.1007/978-1-4939-3046-3_15
10.1371/journal.pone.0076215
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10.1016/j.immuni.2009.11.012
10.1016/j.jcyt.2014.12.002
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10.1038/s41467-019-10366-y
10.1038/s41586-020-1946-0
10.1073/pnas.2217887120
10.3389/fimmu.2019.00340 | [
"Su",
"Anthony-Gonda",
"Orentas",
"Dropulić",
"Goldstein"
] | [
"Departments of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, USA. [email protected].",
"Caring Cross, Gaithersburg, MD, USA.",
"Caring Cross, Gaithersburg, MD, USA.",
"Caring Cross, Gaithersburg, MD, USA.",
"Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA. [email protected].\nDepartments of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, USA. [email protected]."
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Subsets and Splits