Chuan Tong
Yao Wang
Yunhe Gao
Hanren Dai
Yelei Guo
Xudong Zhao
Yi Wang
Zizheng Wang
Weidong Han
Lin Chen
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
Funds: 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).
Received Date: 2016-12-20
Rev Recd Date:2017-01-31
Abstract
Abstract
Human epidermal growth factor receptor 2 (HER2) proteins 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 targets for the clinical treatment of patients with HER2-positive GC. Despite improvements in survival, numerous HER2-positive patients fail treatment with trastuzumab, 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 CD3ζ moieties. Our findings show that the expanded CAR-T cells, expressing an increased central memory phenotype, were activated by the specific recognition of HER2 antigens in an MHC-independent manner, and effectively killed patient-derived HER2-positive GC cells. In HER2-positive xenograft tumors, CAR-T cells exhibited considerably enhanced tumor inhibition ability, long-term survival, and homing to targets, 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.Keywords: chimeric antigen receptor,
HER2,
gastric cancer,
cancer stem cell,
CD137,
immunotherapy
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