Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Department of Pain Treatment, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Int J Mol Sci. 2023 May 23;24(11):9115. doi: 10.3390/ijms24119115.
Chimeric antigen receptor T cell (CAR-T) therapy in hematologic malignancies has made great progress, but there are still some problems. First, T cells from tumor patients show an exhaustion phenotype; thus, the persistence and function of the CAR-Ts are poor, and achieving a satisfactory curative effect is difficult. Second, some patients initially respond well but quickly develop antigen-negative tumor recurrence. Thirdly, CAR-T treatment is not effective in some patients and is accompanied by severe side effects, such as cytokine release syndrome (CRS) and neurotoxicity. The solution to these problems is to reduce the toxicity and enhance the efficacy of CAR-T therapy. In this paper, we describe various strategies for reducing the toxicity and enhancing the efficacy of CAR-T therapy in hematological malignancies. In the first section, strategies for modifying CAR-Ts using gene-editing technologies or combining them with other anti-tumor drugs to enhance the efficacy of CAR-T therapy are introduced. The second section describes some methods in which the design and construction of CAR-Ts differ from the conventional process. The aim of these methods is to enhance the anti-tumor activity of CAR-Ts and prevent tumor recurrence. The third section describes modifying the CAR structure or installing safety switches to radically reduce CAR-T toxicity or regulating inflammatory cytokines to control the symptoms of CAR-T-associated toxicity. Together, the knowledge summarized herein will aid in designing better-suited and safer CAR-T treatment strategies.
嵌合抗原受体 T 细胞（CAR-T）疗法在血液恶性肿瘤中取得了重大进展，但仍存在一些问题。首先，肿瘤患者的 T 细胞表现出衰竭表型；因此，CAR-T 的持久性和功能较差，难以达到满意的疗效。其次，一些患者最初反应良好，但很快出现抗原阴性肿瘤复发。第三，CAR-T 治疗在一些患者中无效，并伴有严重的副作用，如细胞因子释放综合征（CRS）和神经毒性。解决这些问题的方法是降低 CAR-T 治疗的毒性并提高其疗效。本文描述了降低血液恶性肿瘤中 CAR-T 治疗毒性和提高疗效的各种策略。在第一节中，介绍了使用基因编辑技术修饰 CAR-T 或与其他抗肿瘤药物联合使用以增强 CAR-T 治疗效果的策略。第二节描述了 CAR-T 设计和构建不同于常规过程的一些方法。这些方法的目的是增强 CAR-T 的抗肿瘤活性并防止肿瘤复发。第三节描述了修饰 CAR 结构或安装安全开关以从根本上降低 CAR-T 毒性或调节炎症细胞因子以控制 CAR-T 相关毒性的症状。总之，本文总结的知识将有助于设计更合适和更安全的 CAR-T 治疗策略。
