Targeting glycosylated antigens on cancer cells using siglec‐7/9‐based CAR T‐cells

Abstract

Chimeric antigen receptor (CAR) T-cells treatment demonstrate the increasing and powerful potential of immunotherapeutic strategies, as seen mainly for hematological malignancies. Still, efficient CAR-T cell approaches for the treatment of a broader spectrum of tumors are needed. It has been shown that cancer cells can implement strategies to evade immune response that include 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. In this regard, siglec-7 and -9 are found on immune cells, such as natural killer cells, T-cells, and dendritic cells and they can promote immune suppression when 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-histocompatibility complex molecule 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 exemplifying the potential of the present approach.Overall, this study demonstrates the benefit of targeting cancer-associated glycosylation patterns using CAR based on native immune receptors and expressed in human primary T-cells.

Aberrant Sialylation in Cancer: Biomarker and Potential Target for Therapeutic Intervention?

“…Meril et al recently reported a chimeric antigen receptor (CAR) T-cell approach to target cancer-associated glycosylation patterns [ 177 ]. As hypersialylated proteins could be recognized by sialic acid-binding immunoglobulin-type lectins (Siglecs), the authors tuned genetic engineering of T-cells expressing Siglec-based CARs with different chimeric receptors based on the exodomain of human Siglec-7 and Siglec-9 molecules, to enable the recognition and elimination of tumor cells.…”

“…As hypersialylated proteins could be recognized by sialic acid-binding immunoglobulin-type lectins (Siglecs), the authors tuned genetic engineering of T-cells expressing Siglec-based CARs with different chimeric receptors based on the exodomain of human Siglec-7 and Siglec-9 molecules, to enable the recognition and elimination of tumor cells. These S7 CAR or S9 CAR showed a significant antitumor activity in vitro against several cancer cell lines derived from tumors of breast, cervix, lung, pancreatic, prostate and melanoma, and, most importantly, a strong tumor growth delay in a xenograft mouse model of human melanoma [ 177 ].…”

Inhibitory Receptors and Checkpoints in Human NK Cells, Implications for the Immunotherapy of Cancer

“…These molecules can increase NK-cell mediated tumor lysis although less efficiently than specific anti-Siglec-7 antibodies (86). Interestingly, a recent study showed that cells engineered with a Siglec-7-based CAR construct can display efficient anti-tumor activity both in vitro against several tumor cell lines expressing Siglec-7 ligands and in vivo in xenograft murine models (87).…”

Current Status on Therapeutic Molecules Targeting Siglec Receptors

“…Targeting cancer-associated glycosylation patterns of tumor cells can be an effective alternative [77,78]. Recently, the efficacy of Siglec-7/9 derived CAR-T cells in eliminating tumor cells has been tested in vitro (Figure 6), in a non-histocompatibility complex molecule restricted way [79]. Siglecs-7 and -9 are expressed on NK cells, T cells, and dendritic cells and can promote immune suppression when binding to sialylated ligands on targeted cells.…”