Abstract 726: Type-I interferon and epigenetic modulators enhance the anti-tumor efficacy of a dendritic-cell targeting MIP3α-antigen vaccine in the B16F10 mouse model
Authors: Gordy James , Markham Richard 
Published: August 2018

Abstract
Background: The chemokine MIP-3α (CCL20) binds to CCR6 found on immature dendritic cells. DNA vaccines fusing MIP-3α to melanoma-associated antigens have been shown to be effective in therapeutically reducing melanoma tumor burden in mouse models. However, the anti-tumor efficacy was not complete. To optimize the therapy, our laboratory has added agents designed to overcome immunoregulatory mechanisms of the tumor microenvironment. Here, we report that the combination of type-I interferon therapy (IFN) with 5-Aza-2'-deoxycitidine (Aza), which has been shown to prevent silencing of interferon responsive genes, profoundly enhanced the therapeutic anti-melanoma efficacy of a MIP-3α-antigen DNA vaccine. Methods: The current studies utilize the B16F10 syngeneic, transplantable, mouse melanoma model system. The MIP-3α-antigen DNA vaccine is administered intramuscularly (i.m.) into the tibialis muscle, followed immediately by i.m. electroporation. The primary construct utilized includes MIP-3α fused to immunogenic regions of gp100 and tyrosinase related protein 2 (TRP-2). Vaccinations are given thrice at one week intervals, beginning at day 5 post challenge. Two days post vaccination, CpG adjuvant is administered into the vaccinated muscle. Aza is given i.p.at 1mg/kg on the first two vaccination days. IFN therapy is given in a series of one high dose followed by three days of low doses, beginning on the first two vaccination days. Tumor sizes, growth, and survival were all assessed. Vaccine antigens and interferon stimulated gene expression levels were explored by RT-PCR. Results: With this therapeutic protocol, we demonstrate for the first time that the addition of IFN therapy with Aza enhances the anti-tumor efficacy of a MIP-3α-gp100-TRP2 vaccine. Combination therapy has led to significantly reduced tumor burden and overall increases in mouse survival, increasing median survival of vaccine alone by 39% and negative control by 86%. Importantly, this increase in efficacy was dependent on the presence of all three components, including vaccine, IFN, and Aza. All permutations of one or two treatments provided inferior efficacy to the triple therapy. The immunological details of this model are under current investigation. Conclusions: Efficient targeting of antigen to immature dendritic cells with a chemokine fusion vaccine offers a potential alternative approach to the ex vivo dendritic cell antigen loading protocols currently undergoing clinical investigation. Combining this approach with IFN therapy enhanced by Aza treatment significantly improved vaccine efficacy. Further potential therapy optimization currently undergoing investigation offers promise for this line of investigation to become a novel melanoma therapy.
Citation Format: James Gordy, Richard Markham. Type-I interferon and epigenetic modulators enhance the anti-tumor efficacy of a dendritic-cell targeting MIP3α-antigen vaccine in the B16F10 mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 726.