Abstract 2994: Engineered STING-targeting immunotherapy delays B16 melanoma tumor growth and significantly improves animal survival as compared to an immune-checkpoint inhibitor
Authors: Amalfitano Andrea , Alyaqoub Fadel S. , Aldhamen Yasser A. , Abbas Abdulraouf , Pereira-Hicks Cristiane , Godbehere Sarah , Waters Christopher M. 
Published: July 2017

Background: The stimulator of interferon genes (STING) is a cytosolic innate sensor activated by cyclic di-nucleotides (CDNs) including the bacterially derived bis-(3′-5′)-cyclic-dimeric-guanosine monophosphate (c-di-GMP), leading to the induction of type I interferons. We recently published that an engineered adenovirus (Ad) vector delivering a potent, bacterially derived diguanylate cyclase (AdVCA0848) in vivo can generate sustained c-di-GMP levels in vivo and induce beneficial immune responses, including induction of IFN-β, activation of NK cells and DCs, as well as enhance antigen-specific T cell responses. Here, we determined if in vivo use of AdVCA0848 can also induce potent anti-tumor responses. Methods: Experiments to be presented include those that subcutaneously placed 150,000 B16F10 melanoma cells into C57BL/6 mice. On day 7 post tumor implant (PTI), tumor-bearing mice were randomly divided into control groups (receiving intra-tumoral (i.t.) vehicle treatments or Ad controls, ± i.p administration of non-specific antibodies) and experimental groups, (single i.t. administrations with 2x1010 vps of AdVCA0848 alone, or in combination with repeated i.p. administrations of 200 μg of an anti-PD1 antibody (RMP-1-14) on days 7,11,15 and 19 PTI. Results: As compared to appropriate controls, we have repeatedly found that a single i.t. injection of AdVCA0848 significantly slowed B16 tumor growth (p&lt;0.01), a result that correlated with high levels of animal survival (p&lt;0.001). These levels of efficacy significantly exceeded those achieved with lone use of a PD-1 inhibitor. Under these same conditions, combined use of the AdVCA0848 therapy with anti-PD1 treatments trended to further improve animal survival (50% survival at day 27 PTI), as compared to lone use of either therapy (36.4% and 26.7% survival at day 27 PTI for AdVCA0848 and PD-1 treatments, respectively). Multiple innate and adaptive immune response readouts and immunohistological evaluations will be presented. Conclusions: The growth of established B16 melanoma tumors was rapidly inhibited after a single i.t. treatment with the engineered STING activator AdVCA0848, and this efficacy resulted in significant improvements in animal survival, at rates that were also significantly better than those achieved using a PD-1 antagonist. Furthermore, the i.t. administration of AdVCA0848 trended to show further improved efficacy when combined with a PD-1 antagonist, suggesting synergy. The AdVCA0848 platform is a novel, off the shelf immune-therapeutic that can now be justified for use to improve anti-tumor responses in melanoma, augment currently approved FDA immune therapies for melanoma (such as PD-1 targeted therapies), as well may show efficacy in other aggressive cancers.

Citation Format: Andrea Amalfitano, Fadel S. Alyaqoub, Yasser A. Aldhamen, Abdulraouf Abbas, Cristiane Pereira-Hicks, Sarah Godbehere, Christopher M. Waters. Engineered STING-targeting immunotherapy delays B16 melanoma tumor growth and significantly improves animal survival as compared to an immune-checkpoint inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2994. doi:10.1158/1538-7445.AM2017-2994