Switchable control over in vivo CAR T expansion, B cell depletion, and induction of memory
| العنوان: | Switchable control over in vivo CAR T expansion, B cell depletion, and induction of memory |
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| المؤلفون: | Elvira Khialeeva, Lance Sherwood, Ian R. Hardy, Jennifer Ma, Meredith Weglarz, Christopher J. Ackerman, Sung Chang Lee, Sophie Viaud, Brent Benish, Travis S. Young, Eric N. Hampton, Ashley K. Woods, Vanessa Núñez |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America |
| بيانات النشر: | Proceedings of the National Academy of Sciences, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Cytotoxicity, Immunologic, 0301 basic medicine, T-Lymphocytes, medicine.medical_treatment, T cell, Antigens, CD19, Receptors, Antigen, T-Cell, Bioengineering, Biology, Lymphocyte Activation, Immunotherapy, Adoptive, Models, Biological, memory, Mice, 03 medical and health sciences, Immunology and Inflammation, Immune system, In vivo, medicine, Animals, cancer, B cell, B-Lymphocytes, Multidisciplinary, CAR T cell, Immunotherapy, Biological Sciences, medicine.disease, Phenotype, Chimeric antigen receptor, Immunoglobulin Switch Region, 3. Good health, Mice, Inbred C57BL, Leukemia, 030104 developmental biology, medicine.anatomical_structure, PNAS Plus, Models, Animal, Cancer research, Cytokines, Female, immunotherapy, control |
| الوصف: | Significance Chimeric antigen receptor (CAR) T cell therapy represents a powerful strategy in immuno-oncology. Nevertheless, associated life-threatening toxicities and chronic B cell aplasia have underscored the need to control engineered T cells in the patient. To address these challenges, we have previously developed a switchable CAR (sCAR) T cell platform that allows dose-titratable control over CAR T cell activity by using antibody-based switches. Here, we demonstrate in a syngeneic murine model that the switchable platform can impart antitumor efficacy while dissociating long-term persistence from chronic B cell aplasia. Further, the functional reversibility of the switchable platform can be leveraged to incorporate “rest” phases through cyclical dosing of the switch to enable the induction of a robust central memory population for in vivo, on-demand expansion of sCAR T cells. Chimeric antigen receptor (CAR) T cells with a long-lived memory phenotype are correlated with durable, complete remissions in patients with leukemia. However, not all CAR T cell products form robust memory populations, and those that do can induce chronic B cell aplasia in patients. To address these challenges, we previously developed a switchable CAR (sCAR) T cell system that allows fully tunable, on/off control over engineered cellular activity. To further evaluate the platform, we generated and assessed different murine sCAR constructs to determine the factors that afford efficacy, persistence, and expansion of sCAR T cells in a competent immune system. We find that sCAR T cells undergo significant in vivo expansion, which is correlated with potent antitumor efficacy. Most importantly, we show that the switch dosing regimen not only allows control over B cell populations through iterative depletion and repopulation, but that the “rest” period between dosing cycles is the key for induction of memory and expansion of sCAR T cells. These findings introduce rest as a paradigm in enhancing memory and improving the efficacy and persistence of engineered T cell products. |
| تدمد: | 1091-6490 0027-8424 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1bbd9a506d99490d2ef1da7252fe0e8b https://doi.org/10.1073/pnas.1810060115 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....1bbd9a506d99490d2ef1da7252fe0e8b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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