Baysal Mehmet A, Chakraborty Abhijit, Tsimberidou Apostolia M
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
J Cancer Immunol (Wilmington). 2024;6(1):20-28. doi: 10.33696/cancerimmunol.6.080.
The emergence of chimeric antigen receptor T cell (CAR-T cell) therapy has revolutionized cancer treatment, particularly for hematologic malignancies. This commentary discusses developments in CAR-T cell therapy, focusing on the molecular mechanisms governing T cell fate and differentiation. Transcriptional and epigenetic factors play a pivotal role in determining the specificity, effectiveness, and durability of CAR-T cell therapy. Understanding these mechanisms is crucial to improve the efficacy and decrease the adverse events associated with CAR-T cell therapies, unlocking the full potential of these approaches. T cell differentiation in CAR-T cell product manufacturing plays an important role in clinical outcomes. A positive correlation exists between the clinical efficacy of CAR-T cell therapy and signatures of memory, whereas a negative correlation has been observed with signatures of effector function or exhaustion. The effectiveness of CAR-T cell products is likely influenced by T-cell frequency and by their ability to proliferate, which is closely linked to early T cell differentiation. The differentiation process involving distinct T memory cell subsets is initiated upon antigen elimination, indicating infection resolution. In chronic infections or cancer, T cells may undergo exhaustion, marked by continuous inhibitory receptor expression, decreased cytokine production, and diminished proliferative capacity. Other cell subsets, such as CD4 T cells, innate-like T lymphocytes, NKT cells, and cord blood-derived hematopoietic stem cells, offer unique advantages in developing the next-generation CAR-T cell-based therapies. Future research should focus on optimizing T-cell-enhancing approaches and developing strategies to potentially cure patients with hematological diseases and solid tumors.
嵌合抗原受体T细胞（CAR-T细胞）疗法的出现彻底改变了癌症治疗，尤其是对血液系统恶性肿瘤的治疗。本评论讨论了CAR-T细胞疗法的发展，重点关注调控T细胞命运和分化的分子机制。转录和表观遗传因素在决定CAR-T细胞疗法的特异性、有效性和持久性方面起着关键作用。了解这些机制对于提高疗效和减少与CAR-T细胞疗法相关的不良事件至关重要，从而释放这些方法的全部潜力。CAR-T细胞产品制造中的T细胞分化在临床结果中起重要作用。CAR-T细胞疗法的临床疗效与记忆特征之间存在正相关，而与效应功能或耗竭特征之间则观察到负相关。CAR-T细胞产品的有效性可能受T细胞频率及其增殖能力的影响，而这与早期T细胞分化密切相关。涉及不同T记忆细胞亚群的分化过程在抗原消除后启动，表明感染得到解决。在慢性感染或癌症中，T细胞可能会发生耗竭，其特征是持续表达抑制性受体、细胞因子产生减少和增殖能力下降。其他细胞亚群，如CD4 T细胞、固有样T淋巴细胞、自然杀伤T细胞和脐带血来源的造血干细胞，在开发下一代基于CAR-T细胞的疗法中具有独特优势。未来的研究应专注于优化T细胞增强方法，并制定策略以潜在治愈血液系统疾病和实体瘤患者。
