Mondal et al. investigated if CAR T cell homing to bone marrow was improved by enforcing expression of the E-selectin ligand sLeX on cultured CAR T cells. Production of CAR T cells from human naive T cells under standard conditions reduced surface sLeX display on both CD4+ and CD8+ T cells, resulting in a profound loss of rolling/tethering ability on E-selectin-expressing endothelial cells. Enzymatic fucosylation greatly increased levels of sLeX, restoring adhesive interactions in vitro under hemodynamic shear without impacting cytotoxic function. In mice, fucosylation improved homing to bone marrow by ~10-fold, suggesting potentially increased potency.
Contributed by Katherine Turner
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. Though 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.
Author Info: (1) Brigham and Women's Hospital, Harvard Medical School, United States. (2) Brigham and Women's Hospital, Harvard Medical School, United States. (3) Massachusetts General Hospital
Author Info: (1) Brigham and Women's Hospital, Harvard Medical School, United States. (2) Brigham and Women's Hospital, Harvard Medical School, United States. (3) Massachusetts General Hospital, Harvard Medical School, United States. (4) Massachusetts General Hospital, Harvard Medical School, United States. (5) Brigham and Women's Hospital, Harvard medical School, United States.
