title: Combination GITR targeting/PD-1 blockade with vaccination drives robust antigen-specific antitumor immunity.
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.
authors.affiliation: Oncology Discovery, Janssen Research and Development, Spring House, PA 19477, USA.
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Villarreal
authors.affiliation: Oncology Discovery, Janssen Research and Development, Spring House, PA 19477, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Chin
authors.affiliation: Oncology Discovery, Janssen Research and Development, Spring House, PA 19477, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Smith
authors.affiliation: Oncology Discovery, Janssen Research and Development, Spring House, PA 19477, USA.
authors.forename: Leopoldo L
authors.initials: LL
authors.lastname: Luistro
authors.affiliation: Oncology Discovery, Janssen Research and Development, Spring House, PA 19477, USA.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Snyder
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage*; D049109:Cell Proliferation; D005260:Female; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000037:antagonists & inhibitors*; D007167:Immunotherapy; D008546:Melanoma, Experimental / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014611:Vaccination
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D053450:Glucocorticoid-Induced TNFR-Related Protein; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; C106544:Tnfrsf18 protein, mouse
keywords: GITR; PD-1; immuno-oncology; immunotherapy; vaccines