The past decade has seen enormous progress in cancer immunotherapy. Checkpoint inhibitors are a class of immunotherapy that act to recruit endogenous T cells of a patient's immune system against cancer-associated peptide- MHC antigens. In this process, mutated antigenic peptides referred to as neoantigens often serve as the target on cancer cells that are recognized by the T cell receptor (TCR) on endogenous T cells. Another successful immunotherapy has involved adoptive T cell therapy, where therapeutic doses of T cells expressing a gene for an anti-cancer receptor are delivered to a patient. This approach has been used primarily against hematopoietic cancers using synthetic receptors called chimeric antigen receptors (CARs). CARs typically contain an antibody fragment (single-chain Fv, scFv) against a cancer cell surface antigen such as the B cell molecule CD19. While therapeutic CARs (and full antibodies) target antigens expressed on cell surfaces, TCRs can target a much larger array of intracellular proteins by binding to any cellular peptide associated with an MHC product. These cancer targets include self-peptides from aberrantly expressed/overexpressed proteins or neoantigens. In this review, we discuss the use of TCRs in adoptive T cell therapy and their target antigens. We focus on two properties that impact sensitivity, potency, and possible toxic cross-reactivity of TCR-mediated therapy: (1) the affinity of the TCR for the target antigen, and (2) the density of the target antigen. Finally, we provide a comprehensive listing of the current clinical trials that involve TCRs in adoptive T cell cancer therapy.

中文翻译：

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用于过继性 T 细胞治疗中基因转移的 T 细胞受体。


过去十年，癌症免疫治疗取得了巨大进展。检查点抑制剂是一类免疫疗法，可招募患者免疫系统的内源性 T 细胞来对抗癌症相关肽 - MHC 抗原。在此过程中，被称为新抗原的突变抗原肽通常作为癌细胞的靶标，被内源性 T 细胞上的 T 细胞受体 (TCR) 识别。另一种成功的免疫疗法涉及过继性 T 细胞疗法，将表达抗癌受体基因的治疗剂量的 T 细胞递送给患者。这种方法主要用于使用称为嵌合抗原受体（CAR）的合成受体来对抗造血系统癌症。 CAR 通常包含针对癌细胞表面抗原（例如 B 细胞分子 CD19）的抗体片段（单链 Fv、scFv）。虽然治疗性 CAR（和完整抗体）靶向细胞表面表达的抗原，但 TCR 可以通过与与 MHC 产物相关的任何细胞肽结合来靶向更大范围的细胞内蛋白质。这些癌症靶标包括来自异常表达/过度表达的蛋白质或新抗原的自身肽。在这篇综述中，我们讨论了 TCR 在过继性 T 细胞疗法中的应用及其靶抗原。我们重点关注影响 TCR 介导疗法的敏感性、效力和可能的毒性交叉反应性的两个特性：(1) TCR 对目标抗原的亲和力，以及 (2) 目标抗原的密度。最后，我们提供了当前涉及 TCR 过继性 T 细胞癌症治疗的临床试验的全面列表。