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, 294 (48), 18465-18474

Glycoengineering of Chimeric Antigen Receptor (CAR) T-cells to Enforce E-selectin Binding

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Glycoengineering of Chimeric Antigen Receptor (CAR) T-cells to Enforce E-selectin Binding

Nandini Mondal et al. J Biol Chem.

Abstract

Tissue colonization (homing) by blood-borne cells critically hinges on the ability of the cells to adhere to vascular endothelium with sufficient strength to overcome prevailing hemodynamic shear stress. These adhesive interactions are most effectively engendered via binding of the endothelial lectin E-selectin (CD62E) to its cognate ligand, sialyl Lewis-X (sLe X ), displayed on circulating cells. Although chimeric antigen receptor (CAR) T-cell immunotherapy holds promise for treatment of various hematologic and non-hematologic malignancies, there is essentially no information regarding the efficiency of CAR T-cell homing. Accordingly, we performed integrated biochemical studies and adhesion assays to examine the capacity of human CAR T-cells to engage E-selectin. Our data indicate that CAR T-cells do not express sLe X and do not bind E-selectin. However, enforced sLe X display can be achieved on human CAR T-cells by surface fucosylation, with resultant robust E-selectin binding under hemodynamic shear. Importantly, following intravascular administration into mice, fucosylated human CAR-T cells infiltrate marrow with 10-fold higher efficiency than do unfucosylated cells. Collectively, these findings indicate that custom installation of sLe X programs tissue colonization of vascularly administered human CAR T-cells, offering a readily translatable strategy to augment tissue delivery, thereby lowering the pertinent cell dosing and attendant cell production burden, for CAR T-cell immunotherapy applications.

Keywords: CAR T cell; E-selectin ligand; cancer therapy; fucosyltransferase; glycobiology; glycosylation; immunotherapy; sLeX; sialyl Lewis X; translational glycobiology.

Conflict of interest statement

According to National Institutes of Health policies and procedures, the Brigham and Women's Hospital has assigned intellectual property rights regarding cell surface glycan engineering to R. S., and R. S. has licensed portions of this technology to an entity he has founded (Warrior Therapeutics, LLC), to BioTechne, Inc., and to Mesoblast Ltd. R. S.'s ownership interests were reviewed and are managed by Brigham and Women's Hospital and Partners HealthCare in accordance with their conflict of interest policy

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