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浙江大学学报（医学版）
浙江大学学报（医学版）  2022, Vol. 51 Issue (2): 192-203    DOI: 10.3724/zdxbyxb-2022-0055
专题报道     
嵌合抗原受体T细胞治疗血液系统恶性肿瘤研究进展
胡珂嘉1,2,3,4,黄玥1,2,3,4,胡永仙1,2,3,4,*(),黄河1,2,3,4,*()
1.浙江大学医学院附属第一医院骨髓移植中心，浙江 杭州 310003
2.浙江大学医学中心良渚实验室，浙江 杭州 311121
3.浙江大学血液学研究所，浙江 杭州 310058
4.浙江省干细胞与细胞免疫治疗工程实验室，浙江 杭州 310058
Progress on CAR-T cell therapy for hematological malignancies
HU Kejia1,2,3,4,HUANG Yue1,2,3,4,HU Yongxian1,2,3,4,*(),HUANG He1,2,3,4,*()
1. Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China;
2. Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311121, China;
3. Institute of Hematology, Zhejiang University, Hangzhou 310058, China;
4. Zhejiang Provincial Laboratory for Stem Cell and Immunity Therapy, Hangzhou 310058, China
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摘要：

嵌合抗原受体（CAR）T细胞是血液系统恶性肿瘤的有效治疗方法，其发展经历了针对B细胞性白血病和淋巴瘤的CD19靶向的CAR-T细胞治疗、针对多发性骨髓瘤的B细胞成熟抗原（BCMA）靶向的CAR-T细胞治疗，近年已经开发出针对T细胞性血液系统恶性肿瘤的CD7靶向的CAR-T细胞治疗。另外，与其他血液系统恶性肿瘤相比，针对髓细胞性恶性肿瘤的CAR-T细胞治疗具有更多阻碍，相关研究也更多样化。为获得在临床上更有效和低毒性的CAR-T细胞，国内外学者开发了多靶点CAR-T细胞、通用型CAR-T细胞，以及从多能干细胞经过基因工程方法获得CAR-T细胞、CAR-自然杀伤细胞、CAR-诱导多能干细胞来源的巨噬细胞。我国学者从新型CAR-T细胞的研发到CAR-T细胞治疗临床研究体系的建立均开展了一系列研究。本文介绍CAR-T细胞治疗在B细胞性、T细胞性、髓细胞性血液系统恶性肿瘤等最新临床研究进展，也展望了多靶点、通用型和诱导多能干细胞来源的新型CAR相关细胞治疗的未来发展方向。
关键词： 嵌合抗原受体T细胞;  血液恶性肿瘤;  通用型;  基因编辑;  诱导多能干细胞;  综述    
Abstract:

Chimeric antigen receptor (CAR) T cell therapy is an effective treatment for hematological malignancies, which have experienced the development of CD19 CAR-T cells for B lymphoblastic leukemia and lymphoma, B cell maturation antigen (BCMA) CAR-T cells for multiple myeloid, and more recently, the development of CD7 CAR-T cells for T cell malignancies. There are more obstacles for myeloid malignancies compared to other hematological malignancies in this field, thus concerning researches are in more diverse ways. In order to obtain more effective clinical CAR-T cells with lower side effects, scientists have developed multi-target CAR-T cells, universal CAR-T cells, as well as CAR-T cells, CAR-NK cells, CAR-iMac cells derived from induced pluripotent stem cells (iPSC) by genetic engineering. Chinese scientists have made significant contribution to the invention and manufacture of origin CAR-T cells and the establishment of an intact clinical research system. This review introduces the latest progress involving CAR-T cell therapy for hematological malignancies including B lymphoblastic malignancies, T lymphoblastic malignancies and myeloid malignancies, and also discuss the future developments including multi-target, universal and iPSC-derived CAR-related cell therapy.
Key words: Chimeric antigen receptor T cell    Hematological malignancies    Universal    Gene editing    Induced pluripotent stem cell    Review
收稿日期: 2022-02-15 出版日期: 2022-08-02
CLC:  R73  
基金资助: 国家自然科学基金（81730008，81870153）
通讯作者: 胡永仙,黄河     E-mail: 1313016@zju.edu.cn
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引用本文:

胡珂嘉,黄玥,胡永仙,黄河. 嵌合抗原受体T细胞治疗血液系统恶性肿瘤研究进展[J]. 浙江大学学报（医学版）, 2022, 51(2): 192-203.

HU Kejia,HUANG Yue,HU Yongxian,HUANG He. Progress on CAR-T cell therapy for hematological malignancies. J Zhejiang Univ (Med Sci), 2022, 51(2): 192-203.

链接本文:

https://www.zjujournals.com/med/CN/10.3724/zdxbyxb-2022-0055    或    https://www.zjujournals.com/med/CN/Y2022/V51/I2/192

图 1  CAR的基本结构和CAR-T细胞治疗机制A: CAR的基本结构：包括抗原结合区scFv、铰链区、跨膜段、共刺激域、含免疫受体酪氨酸活化基序且可传递下游信号的CD3ζ; B: CAR-T细胞杀伤肿瘤的机制：可识别特异性抗原的CAR-T细胞与表达相应抗原的肿瘤细胞结合，通过穿孔素/颗粒酶途径、Fas/FasL等途径介导肿瘤细胞裂解，从而发挥杀伤作用. scFv：单链可变区片段；CAR：嵌合抗原受体； FasL：Fas配体.
图 2  CAR-T细胞治疗血液系统恶性肿瘤常用靶点CAR-T细胞治疗常用靶点包括针对髓细胞性血液系统恶性肿瘤的CD123、针对T细胞性血液系统恶性肿瘤的CD7、针对多发性骨髓瘤的BCMA、针对B-ALL/B-NHL的CD19. CAR：嵌合抗原受体；BCMA：B细胞成熟抗原；B-ALL：急性B淋巴细胞白血病；B-NHL：B细胞非霍奇金淋巴瘤.
图 3  双靶点CAR-T细胞示意图并联型CAR系两种针对不同靶点的CAR分子表达在一个T细胞上，串联型CAR为一个CAR分子中同时表达了两种可结合不同靶点的单链可变区片段. CAR：嵌合抗原受体.
图 4  通用型CAR-T细胞制备过程示意图从健康人外周血中分离单个核细胞，通过基因编辑的手段，如敲除表达T细胞受体、MHCⅠ等分子的基因，再转入CAR分子，制备成通用型CAR-T细胞，可进行标准化生产并应用于患者. CAR：嵌合抗原受体；MHC：主要组织相容性复合体.
图 5  iPSC来源的CAR功能细胞制备过程示意图
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