title: Combination of alphavirus replicon particle-based vaccination with immunomodulatory antibodies: therapeutic activity in the B16 melanoma mouse model and immune correlates.
abstract: Induction of potent immune responses to self-antigens remains a major challenge in tumor immunology. We have shown that a vaccine based on alphavirus replicon particles (VRP) activates strong cellular and humoral immunity to tyrosinase-related protein-2 (TRP2) melanoma antigen, providing prophylactic and therapeutic effects in stringent mouse models. Here, we report that the immunogenicity and efficacy of this vaccine is increased in combination with either antagonist anti-CTL antigen-4 (CTLA-4) or agonist anti-glucocorticoid-induced TNF family-related gene (GITR) immunomodulatory monoclonal antibodies (mAb). In the challenging therapeutic setting, VRP-TRP2 plus anti-GITR or anti-CTLA-4 mAb induced complete tumor regression in 90% and 50% of mice, respectively. These mAbs had similar adjuvant effects in priming an adaptive immune response against the vaccine-encoded antigen, augmenting, respectively, approximately 4- and 2-fold the TRP2-specific CD8(+) T-cell response and circulating Abs, compared with the vaccine alone. Furthermore, while both mAbs increased the frequency of tumor-infiltrating CD8(+) T cells, anti-CTLA-4 mAb also increased the quantity of intratumor CD4(+)Foxp3(-) T cells expressing the negative costimulatory molecule programmed death-1 (PD-1). Concurrent GITR expression on these cells suggests that they might be controlled by anti-GITR mAbs, thus potentially explaining their differential accumulation under the two treatment conditions. These findings indicate that combining immunomodulatory mAbs with alphavirus-based anticancer vaccines can provide therapeutic antitumor immune responses in a stringent mouse model, suggesting potential utility in clinical trials. They also indicate that tumor-infiltrating CD4(+)Foxp3(-)PD-1(+) T cells may affect the outcome of immunomodulatory treatments.
authors.affiliation: Authors' Affiliations: AlphaVax, Inc., Research Triangle Park, North Carolina.
authors.forename: Francesca
authors.initials: F
authors.lastname: Avogadri
authors.forename: Roberta
authors.initials: R
authors.lastname: Zappasodi
authors.forename: Arvin
authors.initials: A
authors.lastname: Yang
authors.forename: Sadna
authors.initials: S
authors.lastname: Budhu
authors.forename: Nicole
authors.initials: N
authors.lastname: Malandro
authors.forename: Daniel
authors.initials: D
authors.lastname: Hirschhorn-Cymerman
authors.forename: Shakuntala
authors.initials: S
authors.lastname: Tiwari
authors.forename: Maureen F
authors.initials: MF
authors.lastname: Maughan
authors.forename: Robert
authors.initials: R
authors.lastname: Olmsted
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.forename: Taha
authors.initials: T
authors.lastname: Merghoub
mesh_terms: D000524:Alphavirus / Q000235:genetics*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D005260:Female; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000037:antagonists & inhibitors; D007074:Immunoglobulin G / Q000276:immunology; D007155:Immunologic Factors / Q000494:pharmacology*; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy; D051379:Mice; D010641:Phenotype; D012093:Replicon; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects; D058425:Vaccines, Virus-Like Particle / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007074:Immunoglobulin G; D007155:Immunologic Factors; D058425:Vaccines, Virus-Like Particle; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase