期刊
JCI INSIGHT
卷 3, 期 13, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.99442
关键词
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资金
- NIH Research (NIHR) [RP-2014-05-007]
- Great Ormond Street Biomedical Research Centre [IS-BRC-1215-20012]
- WLBHF
- Children with Cancer [2014/171]
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-CD3 epsilon CAR derived from OKT3, either before or after TALEN-mediated disruption of the endogenous TCR alpha beta/CD3 complex. Only transduction after disrupting assembly of TCR alpha beta/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 CD3 epsilon 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.
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