Effective and persistent antitumor activity of HER2-directed CAR-T cells against gastric cancer cells in vitro and xenotransplanted tumors in vivo  

作　　者：Yanjing Song Chuan Tong Yao Wang Yunhe Gao Hanren Dai Yelei Guo Xudong Zhao Yi Wang Zizheng Wang Weidong Han Lin Chen 

机构地区：[1]Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, China [2]Medical School of Chinese PLA, Beijing 100853, China [3]Bio-therapeutic Department, Chinese PLA General Hospital, Beijing 100853, China [4]Molecular & Immunology Department, Chinese PLA General Hospital, Beijing 100853, China

出　　处：《Protein & Cell》2018年第10期867-878,共12页蛋白质与细胞（英文版）

基　　金：The authors thank all patients who participated and their families, as well as the investigators and staff at this study for their valuable contribution to this study. We＇d like to give a special thanks to Zhiqiang Wu for the construction of plasmids. This study was supported by grants from the National Natural Science Foundation of China （Grant Nos. 81230061, 81402566, 81672319, 81602507, and 81602711）, the Science and Technology Planning Project of Beijing City （No. Z151100003915076） and the key Nursery Project of Chinese PLA General Hospital （16KMZ05） and was partially supported by a grant from the National Basic Science and Development Programme of China （No. 2013BAI01B04）.

摘　　要：Human epidermal growth factor receptor 2 （HER2） pro- teins are overexpressed in a high proportion of gastric cancer （GC） cases and affect the maintenance of cancer stem cell （CSC） subpopulations, which are used as tar- gets for the clinical treatment of patients with HER2- positive GC. Despite improvements in survival, numer- ous HER2-positive patients fail treatment with trastuzu- mab, highlighting the need for more effective therapies. In this study, we generated a novel type of genetically modified human T cells, expressing a chimeric antigen receptor （CAR）, and targeting the GC cell antigen HER2, which harbors the CD137 and CD3/; moieties. Our findings show that the expanded CART cells, expressing an increased central memory phenotype, were activated by the specific recognition of HER2 antigens in an MHC-in- dependent manner, and effectively killed patient-derived HER2-positive GC cells. In HER2-positive xenograft tumors, CART cells exhibited considerably enhanced tumor inhibition ability, long-term survival, and homing totargets, compared with those of non-transduced T cells. The sphere-forming ability and in vivo tumorigenicity of patient-derived gastric cancer stem-like cells, expressing HER2 and the CD44 protein, were also inhibited. Our results support the future development and clinical application of this adoptive immunotherapy in patients with HER2-positive advanced GC.Human epidermal growth factor receptor 2 （HER2） pro- teins are overexpressed in a high proportion of gastric cancer （GC） cases and affect the maintenance of cancer stem cell （CSC） subpopulations, which are used as tar- gets for the clinical treatment of patients with HER2- positive GC. Despite improvements in survival, numer- ous HER2-positive patients fail treatment with trastuzu- mab, highlighting the need for more effective therapies. In this study, we generated a novel type of genetically modified human T cells, expressing a chimeric antigen receptor （CAR）, and targeting the GC cell antigen HER2, which harbors the CD137 and CD3/; moieties. Our findings show that the expanded CART cells, expressing an increased central memory phenotype, were activated by the specific recognition of HER2 antigens in an MHC-in- dependent manner, and effectively killed patient-derived HER2-positive GC cells. In HER2-positive xenograft tumors, CART cells exhibited considerably enhanced tumor inhibition ability, long-term survival, and homing totargets, compared with those of non-transduced T cells. The sphere-forming ability and in vivo tumorigenicity of patient-derived gastric cancer stem-like cells, expressing HER2 and the CD44 protein, were also inhibited. Our results support the future development and clinical application of this adoptive immunotherapy in patients with HER2-positive advanced GC.

关 键 词：chimeric antigen receptor HER2 gastriccancer cancer stem cell CD137 IMMUNOTHERAPY 

分 类 号：Q51[生物学—生物化学] TP334.7[自动化与计算机技术—计算机系统结构]