Oncotarget

Research Papers:

Combination GITR targeting/PD-1 blockade with vaccination drives robust antigen-specific antitumor immunity

Daniel O. Villarreal _, Diana Chin, Melissa A. Smith, Leopoldo L. Luistro and Linda A. Snyder

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Oncotarget. 2017; 8:39117-39130. https://doi.org/10.18632/oncotarget.16605

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Abstract

Daniel O. Villarreal1, Diana Chin1, Melissa A. Smith1, Leopoldo L. Luistro1 and Linda A. Snyder1

1Oncology Discovery, Janssen Research and Development, Spring House, PA 19477, USA

Correspondence to:

Daniel O. Villarreal, email: dovill33@gmail.com

Keywords: vaccines, GITR, PD-1, immunotherapy, immuno-oncology

Received: January 05, 2017     Accepted: March 01, 2017     Published: March 27, 2017

ABSTRACT

Tumor progression is facilitated immunologically by mechanisms that include low antigen expression, an absence of coimmunostimulatory signals, and the presence of regulatory T cells (Tregs), all of which act to suppress and restrict effector T cells in the tumor. It may be possible to overcome these conditions by a combination of modulatory immunotherapy agents and tumor-antigen targeting to activate and drive effective antitumor T cell responses. Here, we demonstrated that co-administration of aGITR and aPD-1 monoclonal antibodies (mAb) in combination with a peptide vaccine (Vax) in mice bearing established tumors significantly delayed tumor growth and induced complete regression in 50% of the mice. This response was associated with increased expansion and functionality of potent Ag-specific polyfunctional CD8+ T cells, reduced Tregs, and the generation of memory T cells. Tumor regression correlated with the expansion of tumor-infiltrating antigen-specific CD8+ effector memory T cells, as depletion of this cell population significantly reduced the effectiveness of the triple combination Vax/aGITR/aPD-1 therapy. These findings support the concept that dual aGITR/aPD-1 combination with cancer vaccines may be a novel strategy against poorly immunogenic tumors.


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