Title: 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.

Authors: Moon, Edmund K; Ranganathan, Raghuveer; Eruslanov, Evgeniy; Kim, Soyeon; Newick, Kheng; O'Brien, Shaun; Lo, Albert; Liu, Xiaojun; Zhao, Yangbing; Albelda, Steven M

Published In Clin Cancer Res, (2016 Jan 15)

Abstract: 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.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.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 coexpression 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.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.

PubMed ID: 26324743

MeSH Terms: Adoptive Transfer/methods; Animals; Antibodies/immunology*; Antigens, Neoplasm/immunology*; Cell Line, Tumor; Cells, Cultured; HLA Antigens/immunology; Humans; Immunotherapy, Adoptive/methods; Lymphocytes, Tumor-Infiltrating/drug effects*; Lymphocytes, Tumor-Infiltrating/immunology; Membrane Proteins/immunology*; Mice; Programmed Cell Death 1 Receptor/antagonists & inhibitors*; Programmed Cell Death 1 Receptor/immunology*; Receptors, Antigen, T-Cell/immunology; T-Lymphocytes/drug effects*; T-Lymphocytes/immunology*