title: Effective and persistent antitumor activity of HER2-directed CAR-T cells against gastric cancer cells in vitro and xenotransplanted tumors in vivo.
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.
authors.affiliation: Department of General Surgery, Chinese PLA General Hospital, Beijing, 100853, China.|Medical School of Chinese PLA, Beijing, 100853, China.
authors.forename: Yanjing
authors.initials: Y
authors.lastname: Song
authors.affiliation: Bio-therapeutic Department, Chinese PLA General Hospital, Beijing, 100853, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Tong
authors.affiliation: Bio-therapeutic Department, Chinese PLA General Hospital, Beijing, 100853, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Chinese PLA General Hospital, Beijing, 100853, China.|Medical School of Chinese PLA, Beijing, 100853, China.
authors.forename: Yunhe
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Bio-therapeutic Department, Chinese PLA General Hospital, Beijing, 100853, China.
authors.forename: Hanren
authors.initials: H
authors.lastname: Dai
authors.affiliation: Bio-therapeutic Department, Chinese PLA General Hospital, Beijing, 100853, China.
authors.forename: Yelei
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of General Surgery, Chinese PLA General Hospital, Beijing, 100853, China.|Medical School of Chinese PLA, Beijing, 100853, China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of General Surgery, Chinese PLA General Hospital, Beijing, 100853, China.|Medical School of Chinese PLA, Beijing, 100853, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Medical School of Chinese PLA, Beijing, 100853, China.
authors.forename: Zizheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Bio-therapeutic Department, Chinese PLA General Hospital, Beijing, 100853, China. hanwdrsw69@yahoo.com.|Molecular & Immunology Department, Chinese PLA General Hospital, Beijing, 100853, China. hanwdrsw69@yahoo.com.
authors.forename: Weidong
authors.initials: W
authors.lastname: Han
authors.affiliation: Department of General Surgery, Chinese PLA General Hospital, Beijing, 100853, China. chenlinbj@vip.sina.com.
authors.forename: Lin
authors.identifier: 0000-0002-5458-2419
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013274:Stomach Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D014407:Tumor Cells, Cultured
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D011948:Receptors, Antigen, T-Cell; C508053:ERBB2 protein, human
keywords: CD137; HER2; cancer stem cell; chimeric antigen receptor; gastric cancer; immunotherapy