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-CTLA-4 or agonist anti-GITR immunomodulatory monoclonal antibodies (mAbs). In the challenging therapeutic setting, VRP-TRP2 plus anti-GITR or anti-CTLA-4 mAb induced complete tumor regression respectively in 90% and 50% of mice. These mAbs had similar adjuvant effects in priming an adaptive immune response against the vaccine-encoded antigen, augmenting respectively ~4- and 2-fold the TRP2-specific CD8+ T-cell response and circulating Abs, compared to 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 intra-tumor CD4+Foxp3- T cells expressing the negative co-stimulatory 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 anti-cancer vaccines can provide therapeutic anti-tumor 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.
- Received December 6, 2013.
- Revision received January 17, 2014.
- Accepted January 28, 2014.
- Copyright © 2014, American Association for Cancer Research.