Antitumor effects and persistence of a novel HER2 CAR T cells directed to gastric cancer in preclinical models.

New immunotherapeutic approaches are urgently needed for gastric cancer due to its poor survival and unsatisfactory treatment. Here we applied the humanized chA21 scfv based chimeric antigen receptor (CAR) modified T cells approach to the HER2 overexpressing gastric cancer treatment. The chA21-4-1BBz CAR T cells specifically exerted Th1 skewed cytokine response and efficient cytolysis of HER2 overexpressing human gastric cancer cells in vitro. Both the cytokine production and cytotoxicity levels were correlated with the level of HER2 surface expression by tumor cells. In established subcutaneous xenograft and peritoneal metastasis models, chA21-4-1BBz CAR T cells dramatically facilitated regression of HER2 overexpressing tumor and prolonged survival of tumor-bearing mice, whereas spared the progression of HER2 low-expressing tumor. Additionally, the capability of these CAR T cells to persist in circulation, as well as specifically home to, and accumulate in tumor sites were identified. Taken together, these results provide the basis for the future clinical investigation of the humanized chA21 scFv based, 4-1BB costimulated CAR T cells for the treatment of gastric cancer, and other HER2-expressing solid tumors.