Memorial Sloan Kettering Cancer Center (MSKCC), Human Oncology and Pathogenesis Program, New York, NY, USA.
Parker Institute for Cancer Immunotherapy, New York, NY, USA.
Nat Rev Drug Discov. 2023 Dec;22(12):996-1017. doi: 10.1038/s41573-023-00809-z. Epub 2023 Oct 27.
The T cell receptor (TCR) complex is a naturally occurring antigen sensor that detects, amplifies and coordinates cellular immune responses to epitopes derived from cell surface and intracellular proteins. Thus, TCRs enable the targeting of proteins selectively expressed by cancer cells, including neoantigens, cancer germline antigens and viral oncoproteins. As such, TCRs have provided the basis for an emerging class of oncology therapeutics. Herein, we review the current cancer treatment landscape using TCRs and TCR-like molecules. This includes adoptive cell transfer of T cells expressing endogenous or engineered TCRs, TCR bispecific engagers and antibodies specific for human leukocyte antigen (HLA)-bound peptides (TCR mimics). We discuss the unique complexities associated with the clinical development of these therapeutics, such as HLA restriction, TCR retrieval, potency assessment and the potential for cross-reactivity. In addition, we highlight emerging clinical data that establish the antitumour potential of TCR-based therapies, including tumour-infiltrating lymphocytes, for the treatment of diverse human malignancies. Finally, we explore the future of TCR therapeutics, including emerging genome editing methods to safely enhance potency and strategies to streamline patient identification.
T 细胞受体 (TCR) 复合物是一种天然存在的抗原传感器，可检测、放大和协调针对源自细胞表面和细胞内蛋白的表位的细胞免疫反应。因此，TCR 能够靶向癌细胞选择性表达的蛋白质，包括新抗原、癌症种系抗原和病毒癌蛋白。因此，TCR 为一类新兴的肿瘤治疗药物提供了基础。在此，我们回顾了使用 TCR 和 TCR 样分子的当前癌症治疗领域。这包括表达内源性或工程 TCR 的 T 细胞的过继细胞转移、TCR 双特异性结合剂和针对与人类白细胞抗原 (HLA) 结合的肽的抗体（TCR 模拟物）。我们讨论了这些治疗药物临床开发所特有的复杂性，例如 HLA 限制、TCR 回收、效力评估和交叉反应的可能性。此外，我们强调了新兴的临床数据，这些数据确立了基于 TCR 的疗法（包括肿瘤浸润淋巴细胞）在治疗多种人类恶性肿瘤方面的抗肿瘤潜力。最后，我们探讨了 TCR 治疗药物的未来，包括安全增强效力的新兴基因组编辑方法和简化患者鉴定的策略。
