尽管嵌合抗原受体(CAR)工程化T细胞的过继转移在某些血液系统恶性肿瘤患者中取得了前所未有的应答率,这种治疗方式还远远没有发挥其巨大的潜力,尤其是在实体癌的背景下。抗原逃逸变体,表达肿瘤相关抗原(TAA)的健康组织的肿瘤外破坏,CAR-T细胞持久性差,功能衰竭的发生代表了一些最突出的障碍,这些障碍限制了CAR-T细胞诱导具有可耐受的不良反应谱的持久缓解的能力。在这次审查中,我们总结了为应对这种瓶颈而开发的主要方法,包括适配器CAR(AdCAR)系统,布尔逻辑门控,表位编辑,细胞内在信号通路的调节,并掺入安全开关以精确控制CAR-T细胞活化。我们还讨论了与共刺激域选择有关的最紧迫的问题,重点是旨在促进CAR-T细胞持久性和最佳抗肿瘤功能的策略。
Although adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells has achieved unprecedented response rates in patients with certain hematological malignancies, this therapeutic modality is still far from fulfilling its remarkable potential, especially in the context of solid cancers. Antigen escape variants, off-tumor destruction of healthy tissues expressing tumor-associated antigens (TAAs), poor CAR-T cell persistence, and the occurrence of functional exhaustion represent some of the most prominent hurdles that limit CAR-T cell ability to induce long-lasting remissions with a tolerable adverse effect profile. In this review, we summarize the main approaches that have been developed to face such bottlenecks, including the adapter CAR (AdCAR) system, Boolean-logic gating, epitope editing, the modulation of cell-intrinsic signaling pathways, and the incorporation of safety switches to precisely control CAR-T cell activation. We also discuss the most pressing issues pertaining to the selection of co-stimulatory domains, with a focus on strategies aimed at promoting CAR-T cell persistence and optimal antitumor functionality.