Affordable Access

deepdyve-link
Publisher Website

Glycoengineering of chimeric antigen receptor (CAR) T-cells to enforce E-selectin binding.

Authors
  • Mondal, Nandini1, 2
  • Silva, Mariana1
  • Castano, Ana P3
  • Maus, Marcela V3
  • Sackstein, Robert4, 2, 5, 6
  • 1 Department of Dermatology and Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, Massachusetts 02115.
  • 2 Program of Excellence in Glycosciences, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
  • 3 Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, Massachusetts 02129.
  • 4 Department of Dermatology and Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, Massachusetts 02115 [email protected]
  • 5 Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
  • 6 Department of Translational Medicine, Herbert Wertheim College of Medicine, and Translational Glycobiology Institute, Florida International University, Miami, Florida 33199.
Type
Published Article
Journal
Journal of Biological Chemistry
Publisher
American Society for Biochemistry and Molecular Biology
Publication Date
Nov 29, 2019
Volume
294
Issue
48
Pages
18465–18474
Identifiers
DOI: 10.1074/jbc.RA119.011134
PMID: 31628196
Source
Medline
Keywords
Language
English
License
Unknown

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. © 2019 Mondal et al.

Report this publication

Statistics

Seen <100 times