RT Journal Article
SR Electronic
T1 Combination of Alphavirus Replicon Particle–Based Vaccination with Immunomodulatory Antibodies: Therapeutic Activity in the B16 Melanoma Mouse Model and Immune Correlates
JF Cancer Immunology Research
JO Cancer Immunol Res
FD American Association for Cancer Research
SP 448
OP 458
DO 10.1158/2326-6066.CIR-13-0220
VO 2
IS 5
A1 Avogadri, Francesca
A1 Zappasodi, Roberta
A1 Yang, Arvin
A1 Budhu, Sadna
A1 Malandro, Nicole
A1 Hirschhorn-Cymerman, Daniel
A1 Tiwari, Shakuntala
A1 Maughan, Maureen F.
A1 Olmsted, Robert
A1 Wolchok, Jedd D.
A1 Merghoub, Taha
YR 2014
UL http://cancerimmunolres.aacrjournals.org/content/2/5/448.abstract
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.