Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Targeted Tumor Vaccines Group, Clinical Cooperation Unit Applied Tumor Immunity, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Oncogene. 2021 Jan;40(2):421-435. doi: 10.1038/s41388-020-01501-x. Epub 2021 Jan 14.
In spite of high rates of complete remission following chimeric antigen receptor (CAR) T cell therapy, the efficacy of this approach is limited by generation of dysfunctional CAR T cells in vivo, conceivably induced by immunosuppressive tumor microenvironment (TME) and excessive antigen exposure. Exhaustion and senescence are two critical dysfunctional states that impose a pivotal hurdle for successful CAR T cell therapies. Recently, modified CAR T cells with an "exhaustion-resistant" phenotype have shown superior antitumor functions and prolonged lifespan. In addition, several studies have indicated the feasibility of senescence delay in CAR T cells. Here, we review the latest reports regarding blockade of CAR T cell exhaustion and senescence with a particular focus on the exhaustion-inducing pathways. Subsequently, we describe what potential these latest insights offer for boosting the potency of adoptive cell transfer (ACT) therapies involving CAR T cells. Furthermore, we discuss how induction of costimulation, cytokine exposure, and TME modulation can impact on CAR T cell efficacy and persistence, while potential safety issues associated with reinvigorated CAR T cells will also be addressed.
尽管嵌合抗原受体 (CAR) T 细胞疗法在完全缓解方面的成功率很高，但该方法的疗效受到体内功能性 CAR T 细胞生成的限制，这可能是由免疫抑制的肿瘤微环境 (TME) 和过度的抗原暴露引起的。衰竭和衰老是两种关键的功能障碍状态，对成功的 CAR T 细胞治疗构成了关键障碍。最近，具有“抗衰竭”表型的改良 CAR T 细胞显示出了优越的抗肿瘤功能和延长的寿命。此外，几项研究表明 CAR T 细胞衰老延迟的可行性。在这里，我们综述了关于用特定方法阻断 CAR T 细胞衰竭和衰老的最新报告，重点介绍了诱导衰竭的途径。随后，我们描述了这些最新进展为增强涉及 CAR T 细胞的过继细胞转移 (ACT) 疗法的效力提供了哪些潜力。此外，我们还讨论了诱导共刺激、细胞因子暴露和 TME 调节如何影响 CAR T 细胞的疗效和持久性，同时还将解决与重新激活的 CAR T 细胞相关的潜在安全问题。
