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.
OBJECTIVE
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.


METHODS
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.
Division of Pulmonary, Allergy, and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania. edmund.moon@uphs.upenn.edu.
Edmund K
EK
Moon
Division of Pulmonary, Allergy, and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania.
Raghuveer
R
Ranganathan
Division of Pulmonary, Allergy, and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania.
Evgeniy
E
Eruslanov
Division of Pulmonary, Allergy, and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania.
Soyeon
S
Kim
Division of Pulmonary, Allergy, and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania.
Kheng
K
Newick
Division of Pulmonary, Allergy, and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania.
Shaun
S
O'Brien
Department of Animal Biology and Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Albert
A
Lo
Abramson Family Cancer Research Institute and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Xiaojun
X
Liu
Abramson Family Cancer Research Institute and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Yangbing
Y
Zhao
Division of Pulmonary, Allergy, and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania.
Steven M
SM
Albelda
D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D000906:Antibodies / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006680:HLA Antigens / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects* / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*
D000906:Antibodies; D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D006680:HLA Antigens; D008565:Membrane Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell