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

摘要

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-in-dependent manner,and effectively killed patient-derived HER2-pssitive GC cells.In HER2-pssitive 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 tumorigeniclty 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.