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浙江大学学报(医学版)  2022, Vol. 51 Issue (2): 175-184    DOI: 10.3724/zdxbyxb-2022-0044
专题报道     
嵌合抗原受体T细胞治疗恶性实体瘤新进展
刘娇1,涂晓璇2,刘璐璐2,*(),方维佳2,*()
常山县人民医院全科医学科,浙江 衢州 324200
浙江大学医学院附属第一医院肿瘤内科 恶性肿瘤预警与干预教育部重点实验室,浙江 杭州 310003
Advances in CAR-T cell therapy for malignant solid tumors
LIU Jiao1,TU Xiaoxuan2,LIU Lulu2,*(),FANG Weijia2,*()
1. Department of General Medicine, People’s Hospital of Changshan County, Quzhou 324200, Zhejiang Province, China;
2. Department of Medical Oncology, the First Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of Malignant Tumor Early Warning and Intervention of Ministry of Education, Hangzhou 310003, China
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摘要:

患者自身T细胞经过嵌合抗原受体(CAR)基因修饰后,不再受主要组织相容性复合物限制,因而可实现对肿瘤靶标高效应答。目前CAR-T细胞治疗已在部分血液系统恶性肿瘤中显示出了较好的疗效,但在实体瘤中的疗效却差强人意,其主要原因包括实体瘤缺乏特异性强的抗原靶标、经过基因工程改造后的T细胞归巢能力不确定以及抑制性肿瘤免疫微环境。临床试验中,研究较多的实体瘤CAR-T细胞治疗靶点有双唾液酸神经节苷脂(GD2)、紧密连接蛋白18亚型2(CLDN18.2)、间皮素、B7同源性3(B7H3)、磷脂酰肌醇蛋白聚糖(GPC)3、表皮生长因子受体变异体(EGFRv)Ⅲ等。CAR-T细胞与溶瘤病毒、酪氨酸激酶抑制剂、程序性死亡蛋白-1单抗等联合治疗可增加其疗效。本文总结了针对CAR-T细胞治疗实体瘤的优化策略,如通过基因编辑增强其活性;添加相应元件的调控使CAR-T细胞的激活更加安全可控;增强CAR-T细胞的持久性等。通过综述CAR-T细胞治疗实体瘤的最新研究进展,以期为实体瘤的临床治疗提供新思路。

关键词: 嵌合抗原受体T细胞恶性实体瘤免疫治疗临床试验综述    
Abstract:

T cells modified by chimeric antigen receptor (CAR) have the advantage of major histocompatibility complex-independent recognition of tumor-associated antigens, so can achieve efficient response to tumor targets. Chimeric antigen receptor (CAR) T cell therapy has shown a good therapeutic effect in hematological malignancies; however, its efficacy is generally not satisfactory for solid tumors. The reasons include the lack of tumor specific antigen target on solid tumors, the uncertainty of homing ability of engineered T cells and the inhibitory immune microenvironment of tumors. In clinical trials, the targets of CAR-T cell therapy for solid tumors are mainly disialoganglioside (GD2), claudin-18 isoform 2 (CLDN18.2), mesenchymal, B7 homolog 3 (B7H3), glypican (GPC) 3 and epidermal growth factor receptor variant Ш (EGFRvШ)Ⅲ. Combination of CAR-T cells with oncolytic viruses, tyrosine kinase inhibitors, and programmed death ligand-1 monoclonal antibodies may increase its efficacy. The CAR-T cell therapy for solid tumors can be optimized through gene editing to enhance the activity of CAR-T cells, adding corresponding regulatory components to make the activation of CAR-T cells safer and more controllable, and enhancing the persistence of CAR-T cells. In this article, we review the latest advances of CAR-T cell therapy in solid tumors to provide new insights for clinical application.

Key words: Chimeric antigen receptor T cell    Malignant solid tumors    Immunotherapy    Clinical trials    Review
收稿日期: 2022-02-17 出版日期: 2022-08-02
CLC:  R73  
基金资助: 国家科技重大专项(2020ZX09201-003)
通讯作者: 刘璐璐,方维佳     E-mail: liululu2001@zju.edu.cn
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引用本文:

刘娇,涂晓璇,刘璐璐,方维佳. 嵌合抗原受体T细胞治疗恶性实体瘤新进展[J]. 浙江大学学报(医学版), 2022, 51(2): 175-184.

LIU Jiao,TU Xiaoxuan,LIU Lulu,FANG Weijia. Advances in CAR-T cell therapy for malignant solid tumors. J Zhejiang Univ (Med Sci), 2022, 51(2): 175-184.

链接本文:

https://www.zjujournals.com/med/CN/10.3724/zdxbyxb-2022-0044        https://www.zjujournals.com/med/CN/Y2022/V51/I2/175

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