Since the β-chain constant region is encoded by either the TRBC1 or TRBC2 gene, normal T cell populations have a mix of the two genotypes, while T cell malignancies tend to skew toward one or the other. Maciocia et al. confirmed this for many T cell malignancies and took advantage of a TRBC1-specific monoclonal antibody to generate and test proof-of-concept CAR-T cells to demonstrate that such therapy selectively eliminates TRBC1+ malignant and healthy T cells, while leaving the TRBC2+ T cell repertoire intact, preserving cellular immunity.
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.