The production of type 1 interferon (IFN) by host cells in response to an invading pathogen is mediated in part through the STING (Stimulator of IFN Genes) receptor. The STING receptor is generally expressed at high levels in immune cells, including dendritic cells. Once activated, it initiates multiple pathways, including interferons and chemokines, leading to the development of an effective tumor antigen-specific T cell adaptive immune response. Bacterial cyclic dinucleotides (CDNs) trigger IFN in a STING-dependent fashion. A compound (ADU-S100) derived from a CDN-based small molecule platform at Aduro was synthesized to test this approach as a therapeutic opportunity. In mouse tumor models, direct injection of ADU-S100 into melanoma, colon and breast tumors profoundly inhibited tumor growth, both locally and systemically, provided protection against tumor regrowth, and significantly inhibited growth of distal tumors. Other studies demonstrate that vaccination with CDN-adjuvanted recombinant protein induced STING-dependent, antigen-specific CD4 and CD8 T cell responses, and correlated with protective immunity in a viral challenge model.

Dr. Dubensky will address the development of CDN-based targeting of the STING receptor (in collaboration with Novartis) and the likely clinical approaches to best leverage this novel mechanism of action. Other programs will also be discussed, including Aduro\’s LADD platform of attenuated strains of Listeria that have been engineered to express tumor-associated antigens and induce specific and targeted immune responses in both preclinical and clinical studies.