Targeting Glycosylated Antigens on Cancer Cells Using Siglec-7/9 Based CAR T-Cells

Chimeric antigen receptor (CAR) T-cells treatments demonstrate the increasing and powerful
potential of immunotherapeutic strategies. Chimeric antigen receptor (CAR) treatment
represents a promising treatment for hematological malignancies using genetically engineered
T-cells. Still, more efforts are needed to develop efficient CAR-T cell approaches for the
treatment of a broader spectrum of tumors. Indeed, cancer cells develop strategies to evade
immune response such as the expression of inhibitory ligands such as hypersialylated proteins
(sialoglycans) on their surface. These may be recognized by Sialic acid-binding
immunoglobulin-type lectins (Siglecs) which are surface receptors found primarily on immune
cells. For example, Siglec-7 and -9 are found on immune cells such as NK cells and dendritic
cells and they can promote immune suppression binding to sialic acids expressed on target
cells.
In the present study, we hypothesized that it is possible to use genetically engineered T-cells
expressing Siglec-based CARs, enabling them to recognize and eliminate tumor cells, in a non
MHC restricted way. Thus, we genetically modified human T-cells with different chimeric
receptors based on the exodomain of human Siglec-7 and -9 molecules and selected optimal
receptors. We then assessed their antitumor activity in vitro demonstrating the recognition of
cell lines from different histologies. These results were confirmed in a tumor xenograft model
in vivo exemplifying the potential of the present approach. Overall, this study demonstrates the
benefit of targeting cancer-associated glycosylation patterns using immune cells receptors
when expressed in human primary T-cells.