Cancer Institute, University College London, London, UK.
Institute of Child Health, University College London, London, UK.
Nat Med. 2017 Dec;23(12):1416-1423. doi: 10.1038/nm.4444. Epub 2017 Nov 13.
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.
成熟 T 细胞癌症通常具有侵袭性、治疗耐药性和预后不良。免疫治疗方法的临床应用受到缺乏区分恶性和健康（正常）T 细胞的靶抗原的限制。与 B 细胞耗竭不同，pan-T 细胞发育不全是非常有毒的。我们报告了一种基于 T 细胞受体β链恒定区 1 和 2（TRBC1 和 TRBC2）的独特表达的新型靶向策略。我们鉴定了一种具有独特 TRBC1 特异性的抗体，并利用它证明正常和病毒特异性 T 细胞群体都包含 TRBC1 和 TRBC2 区室，而恶性肿瘤仅局限于其中之一。作为抗 TRBC 免疫治疗的概念验证，我们开发了抗 TRBC1 嵌合抗原受体（CAR）T 细胞，该细胞在体外和白血病弥散模型小鼠中识别并杀死正常和恶性 TRBC1，但不识别 TRBC2 T 细胞。与靶向整个 T 细胞群体的非选择性方法不同，TRBC 靶向免疫疗法可以消除 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。
