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Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies

2017; Nature Portfolio; Volume: 23; Issue: 12 Linguagem: Inglês

10.1038/nm.4444

1546-170X

Paul Maciocia, Patrycja Wawrzyniecka, Brian Philip, Ida Ricciardelli, Ayse U. Akarca, Shimobi Onuoha, Mateusz Legut, David K. Cole, Andrew K. Sewell, Giuseppe Gritti, Joan Somja, Miguel Á. Piris, Karl S. Peggs, David C. Linch, Teresa Marafioti, Martin Pulé,

Lymphoma Diagnosis and Treatment

Pule and colleagues identify the TCR β-chain constant region as a new target for chimeric antigen receptor (CAR) T cells in treatment of T cell cancers while potentially preserving a healthy T cell repertoire. They demonstrate that anti-TCRB1 CAR T cells eliminate cancerous TCRB1+ T cells while sparing nearly one-third of normal TCRB2+ T cells. 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 β-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.