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

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 recepto...

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Bibliographic Details
Published in:Clinical cancer research 2016-01, Vol.22 (2), p.436-447
Main Authors: Moon, Edmund K, Ranganathan, Raghuveer, Eruslanov, Evgeniy, Kim, Soyeon, Newick, Kheng, O'Brien, Shaun, Lo, Albert, Liu, Xiaojun, Zhao, Yangbing, Albelda, Steven M
Format: Article
Language:English
Subjects:
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
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Summary: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.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-15-1070