Based on the highly specific 2G12-2B2 antibody, Zingg et al. generated a fully human CAR targeting sialyl-Thomsen-Nouveau antigen (STn), which was expressed at high levels in colon, pancreatic, and gynecological cancers compared to healthy tissues. In vitro, CAR T cells with CD28 and 4-1BB costimulatory domains, but not TRuC constructs, were cytotoxic over longer periods of time, even at low effector:target cell ratios or at native antigen expression levels. In mice, CAR T cells with CD28 showed increased tumor infiltration and induced long-term tumor control and some cures, without considerable toxicity, despite some luminal expression of STn in healthy gastrointestinal tissues.
Contributed by Lauren Hitchings
ABSTRACT: 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. Here, 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 antigen (STn) - was studied with a highly STn-specific antibody across various different tumor tissues. Strong expression was found in a high proportion of gastro-intestinal cancers including pancreatic cancers and in gynecological 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 gastro-intestinal 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.
Author Info: (1) University of Basel, Basel, Switzerland. (2) University of Basel, Basel, Switzerland. (3) University of Basel, Basel, Switzerland. (4) Cancer Immunology, Department of Biomedic
Author Info: (1) University of Basel, Basel, Switzerland. (2) University of Basel, Basel, Switzerland. (3) University of Basel, Basel, Switzerland. (4) Cancer Immunology, Department of Biomedicine, University of Basel, Switzerland. (5) University of Basel, Basel, Switzerland. (6) University of Basel, Basel, Switzerland. (7) University Hospital of Basel, Basel, Switzerland. (8) University of Basel, Basel, Switzerland. (9) Division of Medical Oncology, University Hospital Basel, Basel, Switzerland. (10) University Hospital of Basel, Basel, Switzerland. (11) University of Basel, Basel, Switzerland. (12) University Hospital of Basel, Switzerland. (13) University of Basel, Basel, Switzerland.
