Chimeric Antigen Receptor T Cell Therapy Targeting ICAM-1 in Gastric Cancer

Abstract Cancer therapy utilizing adoptive transfer of chimeric antigen receptor (CAR) T cells has demonstrated remarkable clinical outcomes in hematologic malignancies. However, CAR T application to solid tumors has had limited success, partly due to the lack of tumor-specific antigens and immune-suppressive tumor microenvironment. From the tumor tissues of gastric cancer patients, we found that ICAM-1 expression is significantly associated with advanced stage and shorter survival. Here we report a proof-of-concept study using ICAM-1 targeting CAR T cells against gastric cancer. The efficacy of ICAM-1-CAR T cells showed a significant correlation with the level of ICAM-1 expression in target cells in vitro. In animal models of human gastric cancer, ICAM-1 targeting CAR T cells potently eliminated tumors developed in the lungs, while their efficacy was more limited against the tumors in the peritoneum. To augment CAR T activity against intraperitoneal tumors, combinations with paclitaxel or CAR-activation dependent IL-12 release were explored, and found to significantly increase anti-tumor activity and survival benefit. Collectively, ICAM-1 targeting CAR T cell alone or in combination with chemotherapy is a promising strategy to treat patients with ICAM-1 positive advanced gastric cancer.In this study, we demonstrated therapeutic potential of CAR T cells targeting ICAM-1 in preclinical models of systemic and intraperitoneal metastases of gastric cancer. A combination with paclitaxel or armoring CAR T cells with inducible IL-12 was found to significantly enhance the treatment effect of CAR T cells.