期刊
NATURE MEDICINE
卷 23, 期 12, 页码 1416-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4444
关键词
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资金
- Cancer Research UK
- UK National Institute of Health Research University College London Hospital Biomedical Research Centre
- Kay Kendall Leukaemia Fund [KKL872]
- Innovate UK [102571]
- Innovate UK [102571] Funding Source: UKRI
- National Institute for Health Research [ACF-2011-18-005, CL-2015-18-502] Funding Source: researchfish
Mature T cell cancers are typically aggressive, treatment resistant and associated with poor prognosis. Clinical application of immunotherapeutic approaches has been limited by a lack of target antigens that discriminate malignant from healthy (normal) T cells. Unlike B cell depletion, pan-T cell aplasia is prohibitively toxic. We report a new targeting strategy based on the mutually exclusive expression of T cell receptor beta-chain constant domains 1 and 2 (TRBC1 and TRBC2). We identify an antibody with unique TRBC1 specificity and use it to demonstrate that normal and virus-specific T cell populations contain both TRBC1(+) and TRBC2(+) compartments, whereas malignancies are restricted to only one. As proof of concept for anti-TRBC immunotherapy, we developed anti-TRBC1 chimeric antigen receptor (CAR) T cells, which recognized and killed normal and malignant TRBC1(+), but not TRBC2(+), T cells in vitro and in a disseminated mouse model of leukemia. Unlike nonselective approaches targeting the entire T cell population, TRBC-targeted immunotherapy could eradicate a T cell malignancy while preserving sufficient normal T cells to maintain cellular immunity.
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