Blockade of Programmed Death 1 Augments the Ability of Human T cells Engineered to Target NY-ESO-1 to Control Tumor Growth after Adoptive Transfer

Purpose:Tumor infiltrating lymphocytes (TILs) become hypofunctional, although the mechanisms are not clear. Our goal was to generate a model of human tumor-induced TIL hypofunction to study basic mechanisms and to test anti-human therapeutics. Experimental Design:We transduced human T cells with an optimized T-cell receptor (TCR) that is directed to a peptide within the cancer testis antigen NY-ESO-1. After demonstrating antigen-specific in-vitro activity, these cells were used to target a human lung cancer line that expressed NY-ESO-1 in the appropriate HLA context growing in immunodeficient mice. The ability of anti-human PD1 antibody to augment efficacy was tested. Results:Injection of T cells had some antitumor activity, but did not eliminate the tumors. Injected T cells became profoundly hypofunctional accompanied by upregulation of PD1, Tim3, and Lag3 with co-expression of multiple inhibitory receptors in a high percentage of cells. This model allowed us to test reagents targeted specifically to human T cells. We found that injections of an anti-human PD1 antibody in combination with T cell therapy led to decreased TIL hypofunction and augmented the efficacy of the adoptively transferred T cells. Conclusions:This model offers an efficient platform for preclinical testing of adjuvant immunotherapeutics targeted to human T cells prior to transition to the bedside. Because the model employs engineering of human T cells, but with a TCR clone instead of a CAR, it allows for study of the biology of tumor-reactive TILs that signal through an endogenous TCR. The lessons learned from the TCR-engineered TILs can thus be applied to tumor-reactive TILs.