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Clin Cancer Res. 2016 Jan 15;22(2):436-47. doi: 10.1158/1078-0432.CCR-15-1070. Epub 2015 Aug 31.

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.

Author information

1
Division of Pulmonary, Allergy, and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania. edmund.moon@uphs.upenn.edu.
2
Division of Pulmonary, Allergy, and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania.
3
Department of Animal Biology and Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
4
Abramson Family Cancer Research Institute and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

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 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.

CONCLUSIONS:

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.

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PMID:
26324743
PMCID:
PMC4715990
DOI:
10.1158/1078-0432.CCR-15-1070
[Indexed for MEDLINE]
Free PMC Article

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