嵌合抗原受体(CAR)是单链抗体的可变区和T细胞信号分子的融合蛋白,它使T细胞可以通过非MHC限制性的方式识别特异性抗原,发挥杀伤作用.目前,CAR的信号域已从第一代的单一信号分子发展为包含CD28、4-1BB等共刺激分子的多信号结构域(第二、三代),在体内的存在时间及杀伤能力明显增强.利用靶向CD19和CD20的CAR修饰的T细胞进行过继输注,治疗血液系统恶性肿瘤是目前临床研究的热点.临床试验表明第二代CAR的抗肿瘤能力较第一代CAR明显增强,对于复发及难治性B系肿瘤有一定的疗效.同时,CAR技术也正研究用于骨髓移植后的过继免疫治疗等领域.在治疗安全性方面,目前临床试验中大部分患者对CAR治疗耐受性良好,但学者们对CAR可能引起插入突变、脱靶效应和炎症反应等不良反应也不无忧虑.本文就CAR技术在血液系统恶性肿瘤免疫治疗中的应用及安全性评价作一综述.%Chimeric antigen receptors ( CAR) are fusion proteins between single-chain variable fragments ( scFv) from monoclonal antibodies and signaling domains of T-cells, which allow T-cells recognize specific cell-surface targets in an MHC-unrestricted fashion. The structure of CAR has changed over time, from first generation CAR (scFv + signaling moiety) to 2 and 3 generation CAR (combined with one or multiple costimulatory endodomains, such as CD28, 4-1BB and OX40), which enhance persistence, expansion and cytotoxicity of CAR. Many clinical trials treating hematological malignancies using the CAR-modified T-cells targeting CD19 and CD20 are under evaluation or even finished. These clinical trials indicated that CAR-based immunotherapy prolonged the survival of patients with relapsed/ refractory B-cell malignancies. Furthermore, CAR have being studied to translate to other fields like adoptive therapy after hematopoietic stem cell transplantation. As to the treatment toxicity, CAR modified T-cell infusion is tolerant and safe in most patients. However, insertional mutagenesis, off-target effect and inflammatory response are safety issues surrounding CAR-modified T-cell therapy. In this review, the use of CAR technigue in treatment of hematologic malignancies and evaluation of CAR safety are summarized.
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