嵌合抗原受体修饰T细胞免疫疗法的现状、挑战及应用前景

Current situation,challenge and application prospect of chimeric antigen receptor modified T cell immunotherapy

以嵌合抗原受体修饰T细胞(chimeric antigen receptor T cells,CAR-T)技术为代表的免疫治疗,旨在利用机体免疫细胞的活性特异性地杀灭含有某种抗原表型的恶性肿瘤细胞。CAR-T免疫疗法已成为继外科手术、放射治疗和化疗后最有潜力的肿瘤治疗方法,是利用经基因工程修饰的、可表达嵌合抗原受体(chimeric antigen receptor,CAR)的T细胞进行过继性免疫治疗的技术。CAR-T能够以非限制性形式特异识别肿瘤细胞表面特异抗原并进行杀灭,且无需抗原递呈细胞(antigen presenting cell,APC)参与、不受主要组织相容复合体(major histocompatibility complex,MHC)的限制。CAR-T可通过释放穿孔素、颗粒霉素B等直接杀灭肿瘤细胞、募集体内免疫细胞杀灭肿瘤细胞、形成记忆T细胞获得特异性的长效抗肿瘤机制等发挥治疗作用。CAR-T免疫疗法在白血病、淋巴瘤、多发性骨髓瘤治疗中效果显著,对实体肿瘤治疗潜力巨大。但CAR-T免疫疗法会产生脱靶效应和多种不良反应,诸如细胞因子风暴、神经系统毒性和基因修饰致成瘤风险等。国内尚无自体CAR-T或异体CAR-T产品的生产及质量控制相关规范。未来应在制定相关规范及质量标准的基础上,从寻找肿瘤特异性抗原、强化CAR-T产品的识别特异性、优化CAR-T的制备工艺和筛选流程、降低副反应等方面优化CAR-T细胞制剂的应用。本文就CAR-T免疫疗法的原理、在血液系统恶性肿瘤和实体肿瘤治疗中的应用及存在的挑战作一综述,为相关领域的研究和应用提供参考。

Immunotherapy,represented by chimeric antigen receptor modified T cell(CAR-T) technology,aims to specifically kill the malignant tumor cells of a certain antigen phenotype by using the activity of immune cells. CAR-T immunotherapy has become the most potential tumor therapy following surgery,radiotherapy and chemotherapy,which is a technology of adoptive immunotherapy with gene engineering modified T cells expressing CAR. CAR-T can recognize and kill tumor cell surface specific antigen in a non restricted form,which needs no APC participation and is not limited by major histocompatibility complex(MHC). CAR-T can kill tumor cells by releasing perforin and granithromycin B or by collecting immune cells,and obtain specific long-term anti-tumor mechanism by forming memory T cells. CAR-T immunotherapy is effective in the treatment of leukemia,lymphoma and multiple myeloma,and has a great potential in solid tumor treatment. However,off-target effect and various adverse reactions such as cytokine storm,neurotoxicity and risk of tumor formation caused by gene modification are observed in CAR-T immunotherapy. At present,there is no specification for production and quality control of autologous or allogeneic CAR-T products in China. In the future,the application of CAR-T cell preparations should be optimized in terms of finding tumor specific antigen,enhancing the recognition specificity of CAR-T products,optimizing the preparation process and screening process of CAR-T and reducing side effects on the basis of formulating relevant specifications an d quality standards. This article reviews the principle of CAR-T immunotherapy as well as its application and challenge in the treatment of hematological malignancies and solid tumors so as to provide a reference for the research and application of the therapy in the relevant fields.