Pan-cancer GlyTR1 CAR T cells with ‘velcro-like' density-dependent targeting of beta1,6GlcNAc-branched N-glycans

Bispecific antibodies and chimeric antigen receptor (CAR) T-cells are some of the most potent cancer immunotherapeutics in clinical use, yet most cancers remain poorly targetable. High-affinity antibodies required to maximize killing detect low antigen expression in normal tissue, risking ‘on-target, off-cancer' toxicity. This compels identification of cancer-restricted cell surface protein antigens, which are rare and leave most cancers untreatable by CAR T cells. Tumor Associated Carbohydrate Antigens (TACA's) are the most abundant and widespread cancer antigens known but are poorly targetable by antibodies. With funding from the Cancer Moonshot program at NCI, we recently published in Cell a novel pan-cancer immunotherapeutic technology termed Glycan-dependent T cell Recruiter (GlyTR). Unlike antibodies that employ high-affinity ‘key-lock' binding to target cells regardless of antigen density, GlyTR utilizes high-avidity ‘velcro-like' lectin binding to kill cells with high but not low TACA expression. The GlyTR1 bi-specific protein binds beta1,6GlcNAc-branched N-glycans to overcome immunosuppressive mechanisms in the tumor microenvironment and trigger target-density dependent T cell mediated pan-cancer killing without toxicity in mice having human-like TACA expression. Here we report early development of GlyTR1 CAR T cells, which display similar pan-cancer activity.