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

Abstract

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 mechanisms and to test anti-human therapeutics. Experimental Design We transduced human T cells with a published, 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-PD1 antibody to augment efficacy was tested. Results Injection of transgenic T cells had some antitumor activity, but did not eliminate the tumors. The 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-PD1 antibody in combination with T cells led to decreased TIL hypofunction and augmented the efficacy of the adoptively transferred T cells. Conclusion This model offers a 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 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 TCR-engineered TILs can thus be applied to tumor-reactive TILs.

Development of CAR T cells designed to improve antitumor efficacy and safety

“…In syngeneic pre-clinical models, adoptively transferred T cells show upregulation of PD-1, TIM-3 and LAG-3 and combining cell therapy with PD-1 blockade increases antitumor efficacy of CAR T cells (John et al, 2013) and TILs (Moon et al, 2016). Important results are expected from the first clinical trial combining CAR T cells with CTLA-4 blockade (NCT00586391).…”

Enhancement of PSMA-Directed CAR Adoptive Immunotherapy by PD-1/PD-L1 Blockade

“…We suggest that anti-hPD1 antibody treatment combined with anti-hPSMA CAR human T cells had enhanced killing capacity and cytokine function against Myc-CaP:hPSMA(+) tumors, although the treatment response was comparatively short in duration. Recent literature40, 66 demonstrates that adoptive immunotherapy using genetically modified T cells in combination with PD-1 checkpoint blockade can enhance the antitumor effects of CAR T cells against established subcutaneous tumors in an immune compromised host. Nevertheless, our results indicate that other immune modulation mechanisms exist and restrict CAR T cell targeting, function, and persistence in hPSMA expressing Myc-CaP tumors.…”

Chimeric antigen receptors: driving immunology towards synthetic biology

“…Some aim to further alter the function and/or persistence of the engineered T cell, while others act on the tumor cell or the tumor microenvironment; some approaches integrate the two goals. The molecules used in this setting include cytokines, such as interleukin-7, 12 and 15 [61–64], cytokine receptors [65,66], chimeric costimulatory receptors [67,68], costimulatory ligands [59,69] and other modulators of T cell activation [70,71]. A discussion of the rationale for each one of these designs is beyond the scope of this review, but this diversity reflects the enormous potential of combining immunological and synthetic biology principles for the further improvement of CAR T cells.…”