Combination of alphavirus replicon particle-based vaccination with immunomodulatory antibodies: Therapeutic activity in the B16 melanoma mouse model and immune correlates Journal Article

   

Authors:	Avogadri, F.; Zappasodi, R.; Yang, A.; Budhu, S.; Malandro, N.; Hirschhorn-Cymerman, D.; Tiwari, S.; Maughan, M. F.; Olmsted, R.; Wolchok, J. D.; Merghoub, T.
Article 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. (C) 2014 AACR.
Keywords:	pd-1; regulatory t-cells; responses; antitumor immunity; tumor-immunity; blockade; semliki-forest-virus; suppressor-cells; dna vaccines; cancer
Journal Title:	Cancer Immunology Research
Volume:	2
Issue:	5
ISSN:	2326-6066
Publisher:	American Association for Cancer Research
Date Published:	2014-05-01
Start Page:	448
End Page:	458
Language:	English
ACCESSION:	WOS:000340034200008
DOI:	10.1158/2326-6066.cir-13-0220
PROVIDER:	wos
PUBMED:	24795357
PMCID:	PMC4406637
Notes:	Article -- Source: Wos

https://synapse.mskcc.org/synapse/works/has_related_data_chk/58198