Targeting Cancer-Associated Glycosylation for Adoptive T-cell Therapy of Solid Tumors

Abstract

Chimeric antigen receptor (CAR) T-cell therapy has improved outcomes for patients with chemotherapy-resistant B-cell malignancies. However, CAR T-cell treatment of patients with solid cancers has been more difficult, in part because of the heterogeneous expression of tumor-specific cell surface antigens. In this study, we describe the generation of a fully human CAR targeting altered glycosylation in secretory epithelial cancers. The expression of the target antigen-the truncated, sialylated O-glycan Sialyl-Thomsen-nouveau (STn) antigen-was studied with a highly STn-specific antibody across various different tumor tissues. Strong expression was found in a high proportion of gastrointestinal cancers, including pancreatic cancers, and in gynecologic cancers, in particular ovarian and endometrial tumors. T cells expressing anti-STn CAR were tested in vitro and in vivo. Anti-STn CAR T cells showed activity in mouse models, as well as in assays with primary ovarian cancer samples. No considerable toxicity was observed in mouse models although some intraluminal expression of STn was found in gastrointestinal mouse tissue. Taken together, this fully human anti-STn CAR construct shows promising activity in preclinical tumor models, supporting its further evaluation in early clinical trials.