Glycan-directed CAR-T cells

Abstract

Cancer immunotherapy is rapidly advancing in the treatment of a variety of hematopoietic cancers, including pediatric acute lymphoblastic leukemia and diffuse large B cell lymphoma, with chimeric antigen receptor (CAR)-T cells. CARs are genetically encoded artificial T cell receptors that combine the antigen specificity of an antibody with the machinery of T cell activation. However, implementation of CAR technology in the treatment of solid tumors has been progressing much slower. Solid tumors are characterized by a number of challenges that need to be overcome, including cellular heterogeneity, immunosuppressive tumor microenvironment (TME), and, in particular, few known cancer-specific targets. Post-translational modifications that differentially occur in malignant cells generate valid cell surface, cancer-specific targets for CAR-T cells. We previously demonstrated that CAR-T cells targeting an aberrant O-glycosylation of MUC1, a common cancer marker associated with changes in cell adhesion, tumor growth and poor prognosis, could control malignant growth in mouse models. Here, we discuss the field of glycan-directed CAR-T cells and review the different classes of antibodies specific for glycan-targeting, including the generation of high affinity O-glycopeptide antibodies. Finally, we discuss historic and recently investigated glycan targets for CAR-T cells and provide our perspective on how targeting the tumor glycoproteome and/or glycome will improve CAR-T immunotherapy.

Human T cell glycosylation and implications on immune therapy for cancer

“…Chimeric antigen receptors (CARs) have been developed that recognize cancer-associated glycan epitopes of glycolipids and glycoproteins, such as the Lewis y antigen (Le y ), the sialyl Tn O-glycan epitope (TAG72), disialoganglioside GD2 and a Tn glycoform of MUC-1. 90 Interfering with the interaction of surface glycans and their lectin receptors, for example by adding antibodies that block tumor-associated glycan-lectin interactions is yet another strategy which is explored as antitumor therapy and several applications look very promising and/or are already used in the clinic. 64,[91][92][93][94] Considering the abundance of Siglec ligands on the surface of tumor cells and the inhibitory nature of many Siglecs, multiple studies have recently been initiated, investigating the effect of altering the levels of sialylation on tumor cells.…”

Improving Immunotherapy Through Glycodesign

“…CAR T-cells have been engineered to target glycan epitopes of glycolipids and glycoproteins aberrantly expressed in cancer including TAG72 (the sialyl Tn O-glycan epitope), the Lewis y antigen (Le y ), the disialoganglioside GD2, and Tn MUC1 ( 256 , 257 ). An early CAR T-cell therapy targeting TAG72 failed to elicit a clinical response possibly due to the CARs murine origin, lack of T-cell co-stimulation, or the affinity of the CC49 anti-sialyl Tn mAb ( 256 , 258 ). A subsequent CAR T-cell therapy against Le y was more successful ( 259 ) showing therapeutic potential in a phase I clinical trial ( 260 ).…”

“…Finally, the Tn and sialyl Tn MUC1 epitopes have been targeted by CAR T-cells using a humanized version of the 5E5 antibody ( 264 ). Although glycan-targeting CAR T-cell therapy has yet to achieve FDA approval, prospects are bright with 10 active phase I and II CAR T-cell trials targeting MUC1 glycoforms alone ( 127 , 256 ).…”

Preclinical Activity of Embryonic Annexin A2-Specific Chimeric Antigen Receptor T Cells Against Ovarian Cancer

“…Hence, CAR T cells that target glycans can potentially reduce on-target, off-tumour side effects, as a result of differential glycosylation between normal cell and tumour cells. However, only a limited number of anti-glycan CAR T cells targets have been explored clinically to date, including TAG72 in colorectal cancer, Lewis Y in acute myeloid leukaemia, and GD2 in neuroblastoma [7].…”