Systemic STING agonist therapy drives expression of interferon stimulated genes and downstream production of cytokines in dogs with solid tumors

Abstract

Background Stimulator of interferon genes (STING) agonist drugs can induce expression of interferon stimulated genes (ISGs) and proinflammatory cytokine production aimed to enhance antitumor immunity. The purpose of the current study was to determine the safety, pharmacokinetic, and systemic and intratumoral pharmacodynamic properties of a novel, intravenously delivered STING agonist in client-owned dogs with cancer. Methods GSK856, a small-molecule dimeric amidobenzimidazole STING agonist, was administered intravenously to dogs with naturally developing tumors. Patients received two doses of GSK856 1week apart, followed by definitive-intent surgical tumor removal. Results 19 dogs diagnosed with various solid tumor types, including malignant melanoma (oral mucosa, n=9; digit, n=1; conjunctiva, n=1), soft tissue sarcoma (5), rhabdomyosarcoma (1), oral fibrosarcoma (1), and mammary squamous cell carcinoma (1), were enrolled. Systemic pharmacokinetic analysis revealed rapid plasma clearance of GSK856 within 30min of bolus administration. Clinical adverse events of fever, lethargy, and nausea were transient. Concurrent elevation in serum cytokines, including interleukin-6, was consistent with cytokine release syndrome following activation of the STING pathway. Transcriptional analyses of pretreatment and post-treatment blood and tumor tissue revealed robust induction of ISGs. Conclusions These data identify tolerated dose levels for a novel, intravenously delivered STING agonist compound that results in on-target effects in systemic and intratumoral immune responses in dogs with solid tumors.