Reprogramming T cells to target glycans and overcome glycan‐mediated immunosuppression for cancer therapy

Abstract

T‐lymphocytes (or T‐cells) exhibit rapid proliferation and cytotoxicity after immune recognition of foreign or non‐self antigens. Cancerous cells can often display mutated peptides that can be recognized as non‐self by the immune system, but a frequent mechanism of tumor escape is loss of the antigen display complexes. Chimeric antigen receptor (CAR) technology allows T‐cells to be genetically engineered with a novel immune receptor (as well as additional pro‐inflammatory or effector molecules) that redirect T‐cell specificity based on the targets of monoclonal antibodies. This genetic engineering allows the manufacturing of billions of T‐cells specific for one tumor‐associated antigen.Previously, we designed a CAR T‐cell therapy that targets the glycopeptide epitope Tn‐MUC1 and demonstrated anti‐tumor efficacy against a variety of tumor histotypes, including T‐cell lymphoma, pancreatic cancer, breast cancer, prostate cancer, and other cancer histotypes. Now, we extend the targeting of Tn‐glycopeptides to an oncofetal form of fibronectin, recognized by the antibody FDC‐6. Tn‐fibronectin‐targeting CAR T‐cells exhibit similar efficacy against PC3 prostate tumors as CAR T‐cells targeting cell surface antigens; however, the mechanism of action of cytotoxicity appears to be different, suggesting that T‐cells targeting extracellular antigens may represent a novel platform for inducing anti‐tumor efficacy. Additionally, CAR T‐cell activity against tumors can be improved through additional engineering approaches, such as the use of enzymatic activity, the generation of immunomodulatory fusion proteins, and secretion of large molecules, such as cytokines and antibodies.