Targeting human γδ T cells as a potent and safe alternative to pan-T cells bispecific cell engagers

Abstract

Over the past decade, an increasing number of immunotherapies aiming to improve the ability of the immune system to effectively eradicate tumor cells have been developed. Among them, targeting effector T cell subsets of the immune system with bispecific antibodies, called T Cell Engagers (TCEs), represents an attractive strategy. TCEs are designed to specifically direct cytotoxic T cells towards tumor cells, thereby inducing a strong activation leading to the lysis of tumor cells. New strategies for targeting specific T-cell subsets are currently being explored. In this study, we investigated the activity of different TCEs on both conventional alpha beta (αβ) T cells and unconventional gamma delta (γδ) T cells. We generated TCE molecules based on camelid single-domain antibodies (VHHs) that target the tumor-associated antigen CEACAM5 (CEA), together with particular T-cell receptor chains (TCRs) or a CD3 domain. The in vitro biological activity of the TCEs against the colon carcinoma cell line LS174T was measured using fresh and cultured human Vγ9Vδ2 and αβ T cells. We showed that Vγ9Vδ2 T cells display stronger antitumor activity in vitro than αβ T cells when activated with a CD3xCEA TCE. Furthermore, restricting T cell activation to Vγ9Vδ2 T cells limits the production of pro-tumor factors and pro-inflammatory cytokines, which are often associated with toxicity in patients. Taken together, these results suggest that Vγ9Vδ2γδ T cell-specific TCEs may represent safe, novel, specific, and effective molecules for improving antitumor immunotherapies.