CAR-T细胞治疗多发性骨髓瘤:问题及对策

The treatment of multiple myeloma by CAR-T cells:the problems and countermeasures

多发性骨髓瘤是骨髓中浆细胞异常增生导致的恶性肿瘤,是第二大常见的血液系统恶性肿瘤。日益增多的生物治疗方法为多发性骨髓瘤治疗提供新的思路和方向,CAR-T细胞疗法更是为复发/难治性多发性骨髓瘤患者带来治愈新希望。已有多种靶向多发性骨髓瘤特异性靶标分子CAR-T细胞在临床试验中显示出较好的疗效,然而CAR-T细胞疗法仍存在疗效持续时间不够长、肿瘤易复发等问题,这可能与CAR-T细胞持续性不足、肿瘤细胞表面抗原表达丢失、抗原逃逸、免疫抑制微环境损害T细胞活性等因素相关。已有临床研究通过优化CAR设计、调整制备过程以产生富含特定T细胞亚群的CAR-T细胞、构建健康志愿者来源的通用型CAR-T细胞、引入修饰基因以调节免疫抑制微环境或改善CAR-T细胞增殖能力等方法来提高CAR-T细胞的效应功能并延长其持续作用时间,通过降低CAR结构中抗体免疫原性、引入开关机制等方法来提高CAR-T细胞疗法安全性。众多研究为多发性骨髓瘤的CAR-T细胞治疗注入新的活力,也为抗肿瘤免疫治疗提供新的方法与选择。

Multiple myeloma,the second most common hematologic malignancy,is caused by the abnormal growth of plasma cells in bone marrow.The increasing number of biological treatment methods provides new ideas for the treatment of multiple myeloma,and CAR-T cell therapy brings the possibility of a cure for relapse/refractory multiple myeloma patients.CAR-T cells targeting different multipke myeloma specific molecules have shown good results in clinical trials.However,insufficient efficacy duration and disease recurrence are still associated with CAR-T cell therapy,which may be associated with persistent CAR-T cells deficiency,loss of tumor cell surface antigen expression,antigen escape and impaired T cell activity in the immunosuppressive microenvironment.Clinical studies have been conducted to improve the effector function and duration of CAR-T cells by optimizing CAR design,adjusting the preparation process to generate CAR-T cells rich in specific T cell subsets,constructing universal CAR-T cells derived from healthy volunteers and introducing modification genes to regulate the immunosuppressive microenvironment or improve the proliferation capacity of CAR-T cells.And clinical studies have been conducted to improve the safety of CAR-T cell therapy by reducing the immunogenicity of antibodies in CAR structures and introducing switching mechanisms.These studies have injected new vigor into the treatment of multiple myeloma and will provide new methods and options for anti-tumor immunotherapy.