Combination of Alphavirus Replicon Particlea??Based Vaccination with Immunomodulatory Antibodies: Therapeutic Activity in the B16 Melanoma Mouse Model and Immune Correlates

摘要

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 familya??related gene (GITR) immunomodulatory monoclonal antibodies (mAb). In the challenging therapeutic setting, VRPa??TRP2 plus anti-GITR or antia??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, antia??CTLA-4 mAb also increased the quantity of intratumor CD4+Foxp3a?? 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+Foxp3a??PD-1+ T cells may affect the outcome of immunomodulatory treatments. Cancer Immunol Res; 2(5); 448a??58. ??2014 AACR .