Stimulator of Interferon Genes (STING) is a critical component of the cytosolic DNA sensing pathway of the innate immune system. STING is activated by cyclic dinucleotides (CDNs), a product of the intracellular enzyme, cyclic GMP-AMP synthase (cGAS), in response to presence of cytosolic DNA, including tumor-derived DNA. Production of type I interferon within the tumor microenvironment (TME), mediated by the STING pathway, leads to the priming and activation of systemic tumor antigen-specific CD8+ T-cell immunity and tumor regression. Therapeutic activation of STING through intratumoral (IT) administration of CDNs results in anti-tumor efficacy and long-lived survival in several mouse syngeneic tumor models. Rational design of synthetic CDN derivatives has shown that certain modifications alter STING binding, increase cellular potency, enhance maturation of human dendritic cells to promote in vitro T cell expansion, and are able to broadly activate all human STING haplotypes. Mechanistic studies in mouse tumor models demonstrate that CDNs mediate anti-tumor immunity by inducing an acute innate immune response, leading to collapse of the injected tumor, and promoting a tumor-specific CD8+ T cell response that protects against tumor re-challenge. Anti-tumor efficacy is enhanced by combination with immune checkpoint inhibitors, informing future clinical development. The ability to elicit innate and adaptive anti-tumor immunity via activation of STING in the TME demonstrates that CDNs have high translational potential for the treatment of patients with advanced/metastatic solid tumors. The design of an ongoing Phase 1 first-in-human clinical study to evaluate the safety, tolerability and possible antitumor activity of ADU-S100 in subjects with cutaneously accessible tumors and lymphomas will also be presented.
Citation Format: Sarah M. McWhirter, Laura Hix Glickman, Tony Desbien, Kelsey Sivick Gauthier, David Kanne, Shailaja Kasibhatla, Jie Li, AnneMarie Culazzo Pferdekamper, George Katibah, Ed Lemmens, Leticia Corrales, Meredith Leong, Chudi Ndubaku, Justin Leong, Leonard Sung, Lianxing Zheng, Charles Cho, Yan Feng, Jeffery M. McKenna, John A. Tallarico, Steven L. Bender, Thomas W. Dubensky, Jr.. STING activation in the tumor microenvironment using a synthetic human STING-activating cyclic dinucleotide induces potent antitumor immunity [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B020.
- ©2016 American Association for Cancer Research.