用于实体瘤治疗的缺氧敏感型CAR-T细胞的研究进展

Progress in construction of hypoxia-sensitive CAR-T cell for solid tumor therapy

嵌合抗原受体T(chimeric antigen receptor T,CAR-T)细胞治疗作为一种肿瘤免疫疗法已经在血液系统肿瘤的临床治疗中取得良好效果。然而,由于实体瘤缺乏肿瘤特异性抗原,大多数CAR-T细胞以同样在机体其他正常组织器官中广泛表达的肿瘤相关抗原作为识别靶点,导致脱靶效应的产生,严重时甚至会危及患者生命。由于脱靶效应的存在,CAR-T细胞治疗在实体瘤治疗领域中的应用受到严重限制。为克服CAR-T细胞治疗中脱靶效应的影响,可以利用肿瘤微环境中氧含量低的特点,设计缺氧敏感型CAR-T细胞,使其仅在乏氧的肿瘤微环境中表达靶向肿瘤相关抗原的CAR,从而避免CAR-T细胞对正常组织器官的“误伤”。本文综述缺氧敏感型CAR-T细胞构建的常用元件和思路,梳理近年来构建缺氧敏感型CAR-T细胞的研究进展,有望加强CAR-T细胞治疗的安全性,提高CAR-T细胞在实体瘤治疗中的效果。

Chimeric antigen receptor T(CAR-T)cell therapy,as a kind of tumor immunotherapy,has made remarkable achievements for the treatment of hematological malignancy.Disappointingly,regarding solid tumors,CAR-T cells generally target tumor-associated antigens that are also widely expressed in normal tissues because of the lack of tumor specific antigen,resulting in on-target off-tumor effects,which may even endanger patients’lives.Measures should be taken to overcome the off-target effects which severely limit the application of CAR-T cell therapy in solid tumors.A feasible strategy is to design hypoxia-sensitive CAR-T cells,which express CAR only in the hypoxic tumor microenvironment.Therefore,the redundant“accidental injury”can be avoided.In this review,common approaches as well as recent advances in the construction of hypoxia-sensitive CAR-T cells were discussed and summarized,which has guiding significance for enhancing the safety of CAR-T cell therapy and promoting the application of CAR-T cell in solid tumors.