Small molecule RIG-I agonists induce innate immune responses, immunogenic tumor cell death and in vivo protective immune responses in a colon carcinoma model
Peter Probst, Helle Jensen, Patrick McGowan, David Peckham, Huyen Dinh, Dan Goldberg, Shawn P. Iadonato and Kristin M. Bedard KINETA- Immuno-Oncology Seattle, WA USA
The efficacy of checkpoint inhibitor immunotherapy is dependent on a pre-existing anti-tumor immune response in cancer patients. Combination therapies with modalities eliciting an effector T cell response against tumor antigens may expand the therapeutic benefit of checkpoint inhibitor-mediated immunotherapy. Activation of RIG-I-like receptor pathways has been shown to elicit immunogenic cell death (ICD) in a variety of tumor models. Kineta has identified a panel of small molecule IRF3-dependent RIG-I agonists that induce ICD in tumor cells. RIG-I knockout cell lines were used to show that the proof-of-concept compound, KIN131A, activates RIG-I-dependent signaling in a manner distinct from RNA ligands, stimulates chemokine/cytokine production by human PBMCs, and induces direct activation of dendritic cells. In colon carcinoma CT26 cells, KIN131A treatment induces release of the danger-associated molecular pattern molecules HMGB1 and ATP, mediates the translocation of calreticulin to the cell surface, and activates the intrinsic apoptosis pathway. Experiments using the CT26 colon carcinoma model were used to characterize KIN131A mediated ICD in vivo. KIN131A and related derivatives identified through SAR inhibited tumor growth, enhanced survival, and caused complete regression of tumor growth in approximately 30% of mice. Mice showing complete tumor regression were resistant to re-challenge for up to at least 6 months after primary tumor implantation. Animals that were responsive to KIN131A treatment also demonstrated an increase in tumor antigen specific T cells compared to tumor-bearing animals. These data demonstrate that our RIG-I agonists activate the innate immune response, induce ICD in tumor cells in vivo, and elicit an anti-tumor memory T cell response that controls tumor growth. 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.
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