UPenn scientists demonstrate the potential of engineered chimeric antigen receptor (CAR) T cells in targeting aberrantly glycosylated cancer-specific proteins in vivo and present these antigens as a novel class of target for tumor therapy with engineered T cells.
CARs are genetically engineered receptors that combine the specific binding domains from a tumor targeting antibody with T cell signaling domains to allow specifically targeted antibody redirected T cell activation. CAR therapies have emerged as a potent tool for hematologic malignancies and several clinical studies have shown its potential in refractory or relapsed B-cell malignancies. However, the full potential of CAR T cell therapy in solid tumors is limited by the availability of cell surface antigens with sufficient cancer-specific expression.
The present study by Prof. Carl June and team sought to address this concern. The team developed a CAR that recognized cancer-associated Tn glycoform (GalNAca1-O-Ser/Thr) of cell membrane mucin MUC1, a neoantigen expressed in a variety of cancers. The CAR developed was based on a monoclonal antibody (5E5) specific to a Tn-MUC1 glycopeptide epitope widely expressed by adenocarcinomas. Anti-Tn-MUC1 CAR T cells demonstrated target-specific cytotoxicity and successfully controlled tumor growth in vitro and in mice models of T cell leukemia and pancreatic cancer. These findings demonstrate the therapeutic efficacy of CAR T cells directed against Tn-MUC1.
The study published in Immunity expands the potential of CAR T cells and offers great promise in targeting cancer-specific neoepitopes formed by aberrant glycosylation for a variety of adenocarcinomas and bone marrow-derived cancers. It also provides the base for a CAR T cell-based clinical trial to target solid tumors that express Tn-MUC1.
Source: Engineered CAR T Cells Targeting the Cancer-Associated Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma. Posey AD Jr. et al., Immunity June 2016. DOI