Immunotherapy combining cancer glycotherapy with checkpoint inhibitors

Cancer cells are mutated cells in a way that their sugar coat is often altered to present tumor-associated carbohydrate antigens (TACA). Sialic acids are 9-carbon-backbone acidic sugars covering sugar chains (glycans) on cell surface glycolipids and glycoproteins. N-glycolylneuraminic acid (Neu5Gc) is a dietary non-human carbohydrate that accumulates on human cancer cells. Neu5Gc is foreign to the human immune system and is immunogenic in humans. Immunotherapy is a common cancer treatment which boosts the body`s natural immune system defenses to fight cancer and many cancer patients today are treated with a combination of therapies that are expected to improve therapy efficacy. Here, we aim to design a combination of two of the common immunotherapies: immune checkpoint blockade (blocking monoclonal antibodies targeting CTLA-4, PD-1) and active cancer vaccine containing multiple Neu5Gc-Sialyl-Tn (Gc-STn) TACA covalently attach to Keyhole limpet hemocyanin (KLH). Neu5Gc-deficient Cmah-KO mice were immunized with Gc-STn-KLH vaccine and treatment of MC-38 syngeneic tumors were evaluated in combination with checkpoint inhibitors (CTLA-4 and PD-1). Mouse serum samples were collected weekly the analyzed by a sialoglycan microarray. We found that the active cancer vaccine (GcSTn-KLH) induced a strong anti-Neu5Gc IgG immune response, and the combination of the two therapies resulted in inhibition of tumor growth and reduction in tumor weight 3 weeks after the tumor inoculation. Altogether, our findings highlight the potential of a combination cancer therapy targeting carbohydrates as a novel treatment regimen.