372 agenT-797, a native allogeneic “off-the-shelf” invariant natural killer T (iNKT) cell therapy product improves effector functions within the tumor microenvironment

Abstract

Background T cell exhaustion is a common phenomenon that occurs in the tumor microenvironment (TME) due to pro-longed exposure of T cells to tumor antigen. This is in part governed by the suppressive microenvironment created by myeloid cells. Immune checkpoint inhibitors have shown promising outcomes in clinical trials treating patients with solid cancer. However, not all patients with cancer respond to checkpoint therapy, demonstrating an unmet need to optimize the current approaches including cell therapies and combina-tion strategies. We show here that agenT-797 can reinvigorate exhausted T-cells and differentially target myeloid cells Methods We developed a multi-platform to evaluate interac-tion of agenT-797 with exhausted antigen-specific T cells and myeloid cells. Briefly, we transduced pan T cells with an NY-ESO-1 specific TCR and co-cultured them for multiple rounds with melanoma cell line, A375 that endogenously expresses HLA-A*02:01 and NY-ESO-1 antigen. Killing capacity, cyto-kine profile and phenotype of T cells were analyzed at each round of antigen exposure. We observed progressively reduced activity with each successive round. To assess whether addition of agenT-797 rescues functional impairment of partially exhausted T cells, we performed co-culture experiments of agenT-797 (or conditioned media) with T cells and A375 cells and monitored tumor cell killing and activation of T cells. In addition, we generated M1 and M2 macrophages and DCs and co-cultured them with agenT-797 to monitor activation and killing.