TCRαβ/CD3 disruption enables CD3-specific antileukemic T cell immunotherapy
| Autor: | Roland Preece, Christos Georgiadis, Waseem Qasim, Jane Rasaiyaah, Ulrike Mock |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
CD3 Complex Receptors Antigen T-Cell alpha-beta T-Lymphocytes T cell Genetic enhancement CD3 Viral vector Mice 03 medical and health sciences Antigen Transduction Genetic Cell Line Tumor medicine Animals Humans Cell Engineering B cell Leukemia Receptors Chimeric Antigen biology Genetic Therapy General Medicine Chimeric antigen receptor 030104 developmental biology medicine.anatomical_structure Cancer research biology.protein Female Immunotherapy Stem cell Research Article Muromonab-CD3 |
| Zdroj: | JCI Insight. 3 |
| ISSN: | 2379-3708 |
| Popis: | T cells engineered to express chimeric antigen receptors (CARs) against B cell antigens are being investigated as cellular immunotherapies. Similar approaches designed to target T cell malignancies have been hampered by the critical issue of T-on-T cytotoxicity, whereby fratricide or self-destruction of healthy T cells prohibits cell product manufacture. To date, there have been no reports of T cells engineered to target the definitive T cell marker, CD3 (3CAR). Recent improvements in gene editing now provide access to efficient disruption of such molecules on T cells, and this has provided a route to generation of 3CAR, CD3-specific CAR T cells. T cells were transduced with a lentiviral vector incorporating an anti-CD3ε CAR derived from OKT3, either before or after TALEN-mediated disruption of the endogenous TCRαβ/CD3 complex. Only transduction after disrupting assembly of TCRαβ/CD3 yielded viable 3CAR T cells, and these cultures were found to undergo self-enrichment for 3CAR+TCR-CD3- T cells without any further processing. Specific cytotoxicity against CD3ε was demonstrated against primary T cells and against childhood T cell acute lymphoblastic leukemia (T-ALL). 3CAR T cells mediated potent antileukemic effects in a human/murine chimeric model, supporting the application of cellular immunotherapy strategies against T cell malignancies. 3CAR provides a bridging strategy to achieve T cell eradication and leukemic remission ahead of conditioned allogeneic stem cell transplantation. |
| Databáze: | OpenAIRE |
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