Abstract 1553: Intratumoral delivery of STING agonist results in radiographic response in spontaneous canine high-grade glioma
Authors: C. Elizabeth Boudreau, Cynthia Kassab, Martina Ott, Chase M. DeRay, Jonathan Levine, Michael Curran, Amy B. Heimberger
Journal: Cancer Research (2021)

Abstract Introduction: STING (stimulator of interferon genes) agonists can increase T cell infiltration into immunologically “cold” tumors such as gliomas through proinflammatory activation of suppressive tumor stroma, re-education of tumor-supportive M2 macrophages toward a proinflammatory M1 phenotype and can reverse the suppressive phenotype of myeloid-derived suppressor cells. Preclinical murine glioma models have not correlated with immunotherapy responses in human glioma subjects in part because of poor correlative immunobiology, but recent “omic” profiling has demonstrated a marked association of spontaneously arising canine gliomas with those in human subjects. Methods: We have created a novel STING agonist IACS-8779 that has shown robust activation of the STING pathway with equivalent or superior systemic anti-tumor responses relative to clinical benchmark compounds in murine models. A dose escalation clinical trial was conducted in client-owned canines (n=4) with newly-diagnosed presumed high-grade glioma identified radiographically on standard MRI sequences obtained on a 3T magnet. Each dog received 2 injections intratumorally at an interval of 4-6 weeks. The dose of IACS-8779 was sequentially increased over the course of the 6 injections from 5ug to 20ug, whereas the injection volume was fixed at 50uL. Injections were targeted to the tumors by image guidance, and injections were performed at a rate of 2uL/minute. Neurological status was monitored during the inter-injection interval. MRI was repeated at intervals of 4-6 weeks and radiographic responses were volumetrically analyzed. Results: All dogs tolerated the injections well with clinical symptoms remaining stable between the first and second injection. The survival times of the first 2 dogs were 2.5 and 9 months from the date of onset of signs, whereas the remaining dogs are still alive. The first dog, treated twice at a dose of 5ug, had progressive disease on serial MRI; whereas the second (5 and 10ug) and third (15 and 20ug) dogs had stable disease. The fourth dog treated at 20ug showed a volumetric change of 0.785cm3 pre-treatment to 0.194cm3 (&amp;gt;75%) after a single dose 5 weeks after the first injection. Conclusion: In support of previously published data showing effectiveness of IACS-8779 for treatment of orthotopic murine tumors (Ager CR, Bioorg Med Chem Lett. 2019), these data indicate that IACS-8779 is well-tolerated for repeated intratumoral injections up to 20ug in 50uL in a large animals (canines) with spontaneous glioma. Further, we have shown that a single injection of 20ug IACS-8779 can produce a radiographic response in a spontaneously arising high-grade glioma in the dog. Citation Format: C. Elizabeth Boudreau, Cynthia Kassab, Martina Ott, Chase M. DeRay, Jonathan Levine, Michael Curran, Amy B. Heimberger. Intratumoral delivery of STING agonist results in radiographic response in spontaneous canine high-grade glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1553.