Effective and persistent antitumor activity of HER2-directed CAR-T cells against gastric cancer cells in vitro and xenotransplanted tumors in vivo |
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Authors: | Yanjing Song Chuan Tong Yao Wang Yunhe Gao Hanren Dai Yelei Guo Xudong Zhao Yi Wang Zizheng Wang Weidong Han Lin Chen |
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Institution: | 1. Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, China2. Medical School of Chinese PLA, Beijing 100853, China3. Bio-therapeutic Department, Chinese PLA General Hospital, Beijing 100853, China4. Molecular & Immunology Department, Chinese PLA General Hospital, Beijing 100853, China |
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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 andCD3ζ 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. |
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Keywords: | chimeric antigen receptor HER2 gastric cancer cancer stem cell CD137 immunotherapy |
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