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

// Daniel O. Villarreal 1 , Diana Chin 1 , Melissa A. Smith 1 , Leopoldo L. Luistro 1 and Linda A. Snyder 1 1 Oncology 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.