Evaluation of the safety and efficacy of sting agonists for downstaging and margin accentuation strategies in a murine model of locally advanced pancreatic cancer

Background: Of patients presenting with LAPC (locally advanced pancreatic cancer), less than a quarter will be down-staged to resectability. STING (Stimulator of interferon genes) ligands induce potent inflammation, and hemorrhagic necrosis in murine tumors. Our group has also previously shown that intra-tumoral injection is effective in murine models of pancreatic cancer. We sought to generate and test their application in a pre-clinical model of LAPC. Methods: PANC-02 cells were used to establish tumors in C57BL/6 mice. Tumors were established in the femoral triangle with encasement of the femoral vessels, and within the distal pancreas. Mice were evaluated by CECT (contrast enhanced CT) at 14–21 days, and injected intra- tumorally with 50-100 μg of the STING ligand CDA (Cyclic Di-adenosine). Mice were re-examined at 3 days post by CECT and gross examination. In an R2 resection model, subcutaneous flank tumors were established with SCC7, and after partial resection, 25 μg of CDA or PBS in Matrigel were applied to the resection bed. Results: PANC-02 cells readily established tumors in the femoral triangle, and in the pancreatic tail. These tumors were noted to encase the femoral and splenic vessels with preserved patency. After intra-tumoral injection of CDA, patency was preserved with no hemorrhagic or thrombotic complications noted on CT or at the time of gross evaluation. In the R2 resection model, CDA treated mice had no evidence of recurrence at 30 days, while PBS treated mice readily recurred. Conclusion: STING ligands represent a novel class of agents that could be used in neoadjuvant, or margin accentuation strategies for LAPC. In an R2 resection model, CDA can prevent recurrence, and in a model of LAPC, initial results suggest CDA is safe. Evaluation of the safety and efficacy of CDA in this setting is ongoing.