A Small Molecule IRF3 Agonist Targeting the RIG-I Pathway Modulates Innate Immune Responses and Induces In Vitro Markers of Immunogenic Cell Death in a Murine Colon Carcinoma Tumor Model
Peter Probst, Patrick McGowan, David Peckham, Nathan Hedin, Huyen Dinh, Dan Goldberg, Shawn P. Iadonato, and Kristin M. Bedard
KINETA, Inc., Seattle, WA USA
The RIG-I innate immune signaling pathway is a key modulator of antiviral immune defense, and nucleic acid agonists of RIG-I have been shown to elicit immunogenic cell death (ICD) in a murine pancreatic tumor model. Kineta has identified small molecule IRF3 immune modulators that activate the RIG-I pathway and induce in vitro signs of ICD in tumor cell lines. The proof of concept compound, KIN131A, activates RIG-I-dependent signaling in reporter cell lines, stimulates chemokine/cytokine production by human PBMCs, and induces activation of dendritic cells. In colon carcinoma CT26 cells, KIN131A treatment causes the release of the danger-associated molecular pattern molecules HMGB1 and ATP, stimulates the translocation of calreticulin from the endoplasmic reticulum to the cell surface, and induces cell death. Together, these data suggest that KIN131A triggers ICD in CT26 cells. Ongoing experiments using the CT26 mouse tumor model are characterizing KIN131A induced ICD in vivo. Preliminary data show that KIN131A inhibits tumor growth, enhances survival and protects a subset of mice from tumor cell re-challenge. These data suggest that small molecule RIG-I agonists can induce ICD in vivo and provide immune mediated anti-tumor properties. The induction of ICD by small molecule RIG-I agonists may provide a unique immunotherapeutic opportunity to induce or boost the antitumor immune response in patients and enhance the efficacy of checkpoint inhibitor-mediated immunotherapy.