PT  - JOURNAL ARTICLE
AU  - Avogadri, Francesca
AU  - Zappasodi, Roberta
AU  - Yang, Arvin
AU  - Budhu, Sadna
AU  - Malandro, Nicole
AU  - Hirschhorn-Cymerman, Daniel
AU  - Tiwari, Shakuntala
AU  - Maughan, Maureen F.
AU  - Olmsted, Robert
AU  - Wolchok, Jedd D.
AU  - Merghoub, Taha
TI  - Combination of Alphavirus Replicon Particle–Based Vaccination with Immunomodulatory Antibodies: Therapeutic Activity in the B16 Melanoma Mouse Model and Immune Correlates
AID  - 10.1158/2326-6066.CIR-13-0220
DP  - 2014 May 01
TA  - Cancer Immunology Research
PG  - 448--458
VI  - 2
IP  - 5
4099  - http://cancerimmunolres.aacrjournals.org/content/2/5/448.short
4100  - http://cancerimmunolres.aacrjournals.org/content/2/5/448.full
SO  - Cancer Immunol Res2014 May 01; 2
AB  - 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. Cancer Immunol Res; 2(5); 448–58. ©2014 AACR.