嵌合抗原受体技术免疫治疗血液系统恶性肿瘤的研究进展  

Advances in Immunotherapy of Hematological Malignancies by Using Chimeric Antigen Receptor-modified Lymphocytes——Review

作　　者：徐晓军[1] 赵海招[1] 汤永民[1] 

机构地区：[1]浙江大学医学院附属儿童医院血液肿瘤科,浙江杭州310003

出　　处：《中国实验血液学杂志》2013年第2期521-525,共5页Journal of Experimental Hematology

基　　金：国家自然科学基金(编号31100638);浙江省自然科学基金(编号Y2110020);教育部博士点基金(编号20110101120138)

摘　　要：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-ceUs 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.

关 键 词：嵌合抗原受体 血液系统肿瘤 免疫治疗 CD19 CD20 

分 类 号：R733[医药卫生—肿瘤]