Yao Catherine D, Davis Kara L
Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplant and Regenerative Medicine, Stanford University, Stanford, CA, USA.
Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
Cancer Metastasis Rev. 2024 Dec 3;44(1):15. doi: 10.1007/s10555-024-10232-4.
Cellular and targeted immunotherapies have revolutionized cancer treatments in the last several decades. Successful cellular therapies require both effective and durable cytotoxic activity from the immune cells as well as an accessible and susceptible response from targeted cancer cells. Correlative studies from clinical trials as well as real-world data from FDA-approved therapies have revealed invaluable insights about immune cell factors and cancer cell factors that impact rates of response and relapse to cellular therapies. This review focuses on the flagship cellular therapy of engineered chimeric antigen receptor T-cells (CAR-T cells). Within the CAR-T cell compartment, we discuss discoveries about T-cell phenotype, transcriptome, epigenetics, cytokine signaling, and metabolism that inform the cell manufacturing process to produce the most effective and durable CAR-T cells. Within the cancer cell compartment, we discuss mechanisms of resistance and relapse caused by mutations, alternative splicing, post-transcriptional modifications, and cellular reprogramming. Continued correlative and mechanistic studies are required to help us further optimize cellular therapies in a variety of malignancies.
在过去几十年中，细胞免疫疗法和靶向免疫疗法彻底改变了癌症治疗方式。成功的细胞疗法既需要免疫细胞具备有效且持久的细胞毒性活性，也需要靶向癌细胞有可及且敏感的反应。来自临床试验的相关性研究以及美国食品药品监督管理局（FDA）批准疗法的真实世界数据，揭示了关于影响细胞疗法反应率和复发率的免疫细胞因子和癌细胞因子的宝贵见解。本综述聚焦于工程化嵌合抗原受体T细胞（CAR-T细胞）这一旗舰细胞疗法。在CAR-T细胞领域，我们讨论了有关T细胞表型、转录组、表观遗传学、细胞因子信号传导和代谢的发现，这些发现为细胞制造过程提供信息，以生产最有效且持久的CAR-T细胞。在癌细胞领域，我们讨论了由突变、可变剪接、转录后修饰和细胞重编程导致的耐药和复发机制。需要持续进行相关性和机制性研究，以帮助我们进一步优化针对各种恶性肿瘤的细胞疗法。
