Preclinical application of a CD155 targeting chimeric antigen receptor T cell therapy for digestive system cancers

Abstract

Despite intensive multimodal therapy, the prognosis for patients with digestive system cancers remains poor. Cancer cell heterogeneity and immunosuppressive microenvironments are the main barriers to the effective CAR-T cell therapy with solid malignancies. In parallel, tumor-associated macrophages (TAMs) are essential for tumor immunosuppressive microenvironment formation. The limited efficacy of CAR-T cell therapy with solid malignancies prompted us to test whether new therapeutic target could enhance the antitumor activity of CAR-T cells with several digestive system cancer types. We determined CD155 expression in multiple human digestive system cancers, including gastric cancer, esophagus cancer, pancreatic cancer, and colon cancer, normal tissue samples and patient-derived M2-like tumor-associated macrophages. We developed a CD155-based CAR comprising the extracellular domain of human TIGIT, 4-1BB, and CD3z signaling domains (BBz). Furthermore, we validated the killing efficacy and safety of CD155-BBz CAR-T cells in vitro and in vivo using in-house established preclinical tumor models. CD155 was strongly and homogenously expressed in digestive system cancers but mildly in normal tissues, indicating it could be an ideal target for CAR-T cell therapy, moreover, TAMs that express CD155 possess an immunosuppressive M2-like profile. We found that CD155-BBz CAR-T cells can mediate significant antitumor activity in vivo, which induces complete tumor regression and long-lasting immunologic memory of established solid tumors in xenograft models. Our study indicates that CD155 is a promising target for digestive system cancer therapy, and CD155-targeting CAR-T cells perform a detecting power in digestive system cancer clinical trials.