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.

中文翻译：

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靶向T细胞受体β链恒定区，用于T细胞恶性肿瘤的免疫治疗。

成熟的T细胞癌通常具有侵略性，抗药性且预后差。免疫治疗方法的临床应用由于缺乏将恶性肿瘤与健康（正常）T细胞区分开来的靶抗原而受到限制。与B细胞耗竭不同，pan-T细胞发育不良具有致命的毒性。我们报告了基于T细胞受体β链恒定域1和2（TRBC1和TRBC2）的互斥表达的一种新的靶向策略。我们鉴定出具有独特TRBC1特异性的抗体，并用它来证明正常和病毒特异性T细胞群体同时含有TRBC1 ⁺和TRBC2 ⁺隔室，而恶性肿瘤仅限于一种。作为抗TRBC免疫疗法概念的证明，我们开发了抗TRBC1嵌合抗原受体（CAR）T细胞，该细胞可在体外和经散布的小鼠模型中识别并杀死正常和恶性的TRBC1 ⁺，但不识别TRBC2 ^+的T细胞。白血病。与靶向整个T细胞群体的非选择性方法不同，靶向TRBC的免疫疗法可以根除T细胞恶性肿瘤，同时保留足够的正常T细胞以维持细胞免疫力。