Targeting glycans for CAR therapy: The advent of sweet CARs

Abstract

Chimeric antigen receptor (CAR) T cell therapy has created a paradigm shift in the treatment of hematologic malignancies but has not been as effective toward solid tumors. For such tumors, the primary obstacles facing CAR T cells are scarcity of tumor-specific antigens and the hostile and complex tumor microenvironment. Glycosylation, the process by which sugars are post-translationally added to proteins or lipids, is profoundly dysregulated in cancer. Abnormally glycosylated glycoproteins expressed on cancer cells offer unique targets for CAR T therapy as they are specific to tumor cells. Tumor stromal cells also express abnormal glycoproteins and thus also have the potential to be targeted by glycan-binding CAR T cells. This review will discuss the state of CAR T cells in the therapy of solid tumors, the cancer glycoproteome and its potential for use as a therapeutic target, and the landscape and future of glycan-binding CAR T cell therapy.

Keywords: CAR T cell therapy; cancer glycobiology; glycan; glycoprotein; solid tumor; tumor microenvironment.

Graphical abstract

Figure 1

Glycosylation patterns in normal and malignant cells Left panel depicts glycosylation patterns found on normal cell-surface glycoproteins, including N-linked glycosylation, which occurs via nitrogen linkages at asparagine (Asn) residues in the consensus sequence Asn-X-serine (S)/threonine (T) (where X is any amino acid except proline), and O-linked glycosylation, which occurs via oxygen linkages at hydroxyl groups of S, T or, much less commonly, tyrosine (Y) residues. Right panel depicts abnormal glycosylation patterns found on cancer cells. These include the truncated O-glycans Tn and STn, sialylated glycans including sialyl Lewis A (sLeA) and sialyl Lewis x (sLeX), and highly branched N-glycans including high-mannose and fucosylated branched N-glycans.

Figure 2

Sweet CAR design Depicted are CAR T cells with a traditional scFv extracellular domain (1), lectin extracellular domain (2), or smart anti-glycan reagent (SAGR; generated from lamprey antibodies) extracellular domain (3), binding to representative abnormal glycoproteins on the surface of cancer cells (in gray), surrounded by the tumor microenvironment (in brown). Inset shows CAR domains.