嵌合抗原受体T细胞治疗实体肿瘤的进展与挑战

Advances and challenges of chimeric antigen receptor T cell therapy for solid tumors

近年来，嵌合抗原受体T细胞（CAR—T）技术的发展使肿瘤免疫治疗成为生物治疗领域热点。CAR—T可识别肿瘤细胞表面抗原、靶向裂解肿瘤细胞。以CD19为代表CAR—T在血液系统肿瘤治疗中取得成功。然而其在实体肿瘤中的应用仍面临巨大挑战。与血液系统肿瘤比较，实体肿瘤微环境更复杂，肿瘤特异性抗原筛选难度大。回输的CAR．T由血液系统浸润至肿瘤局部，需克服肿瘤基质细胞屏障。尽管部分CAR—T可浸润至肿瘤细胞内，但T细胞功能很快被抑制。笔者综合分析现有研究结果，从实体肿瘤抗原特异性、实体肿瘤抗原异质性、CAR—T靶向肿瘤部位以及肿瘤微环境对CAR—T治疗的抑制作用等方面重点探讨影响实体肿瘤CAR—T疗效的免疫抑制因素及其可能的解决方法。笔者相信，以基因工程为代表的生物技术发展必将为优化CAR—T结构和功能提供更为丰富的技术手段，实体肿瘤CAR—T治疗必将取得突破性进展。

In recent years, cancer immunotherapy has attracted considerable attention in the field of biotherapy for the development of chimeric antigen receptor T （CAR-T） cell. CAR-T cells are capable of recognizing tumor cell surface antigens leading to kill tumor cells. Anti-CD19 CAR-T has achieved remarkable success in the treatment of hematopoietic malignancies. Whether it can benefit solid tumor patients to the same extent still faces great challenges, and it has been a focus of attention in immunotherapy for tumors. Compared with hematological malignancies, the microenvironment of solid tumor is more complex, and the screening of tumor specific antigen is more difficult. The infihration of CAR-T ceils from the blood system to the tumor site needs to overcome the tumor stromal barrier. Although part of CAR-T cells can infiltrate into tumor site, its function may be quickly inhibited by multiple factors in microenvironment. In this paper, authors discussed the challenges that CAR-T is facing for solid tumor treatment, including the specificity of the tumor antigen, the heterogeneity of the solid tumor antigen and the inhibitory effect of the tumor microenvironment, and proposed potential strategies to possibly overcome these hurdles. Authors believe that with the development of biotechnology, it will provide more abundant technical means to optimize the structure and function of CAR-T, and CAR-T will make breakthrough progress in the treatment of solid tumor.