Abstract 592: Demonstration of E7766, a novel STING agonist, as a potent immunotherapy in BCG-insensitive non-muscle invasive bladder cancer models via intravesical administration
Authors: Huang Kuan-Chun , Zhang Chi , Yu Kun , Kim Dae-Shik , Dixit Vaishali , Hukkanen Renee , Choi Hyeong-Wook , Hutz Janna , Fang Frank , Bao Xingfeng 
Published: September 2020

Abstract
Introduction: Calmette-Guerin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) is a significant unmet medical need. We report pharmacological, pharmacodynamic and pharmacogenomic characterization of E7766, a novel STING (stimulator of interferon genes) agonist, as a potent immunotherapy in BCG-insensitive orthotopic murine NMIBC models via intravesical administration. To our knowledge, this is the first demonstration of activity of a STING agonist in NMIBC tumor model.
Methods: E7766 was examined for antitumor activity in two orthotopic murine NMIBC tumor models via intravesical administration and comparatively characterized in STING activation activity in primary human PBMC cells with defined STING genotypes. Local and systemic pharmacodynamic biomarker changes in tumor-bearing model were identified.
Results: E7766, from a structurally novel class of macrocyclic STING agonists, showed specific and potent agonist activity in both human and mouse STING. In human PBMCs, E7766 demonstrated potent and consistent activity across seven tested human STING genotypes. By contrast, a reference cyclic dinucleotide STING agonist showed substantial variability, and was inactive in the REF-REF genotype. Intravesical administration of E7766 to two orthotopic murine models for BCG-insensitive NMIBC showed a dose-dependent and curative activity without serious adverse effects. In contrast, anti-PD1 treatment was ineffective in both models. Tumor-free animal derived from E7766 treatment completely rejected rechallenge of the same tumor cells, demonstrating establishment of effective tumor-specific memory immune response in those compound-treated animals. The anti-tumoral activity was accompanied with activation of IFN pathway, T cell infiltration, NK activity and antigen presentation in bladder wall, and robust induction of IFNβ, CXCL10 and other downstream effectors of STING activation inside the bladder cavity and in urine. Notably, the IFNβ gene induction was found in bladder, but not in blood from treated animals indicative of a primarily local STING activation by intravesical E7766, which was consistent with low systemic bioavailability of the compound via the administration route.
Conclusions: These preclinical studies demonstrated a potent anti-tumor activity and induction of tumor-specific memory response by intravesically administered STING agonist E7766 in orthotopic murine models for BCG- and anti-PD1-insensitive NMIBC. A clinical study for intravesical E7766 in NMIBC patients has been initiated (NCT04109092) in North America.
Citation Format: Kuan-Chun Huang, Chi Zhang, Kun Yu, Dae-Shik Kim, Vaishali Dixit, Renee Hukkanen, Hyeong-Wook Choi, Janna Hutz, Frank Fang, Xingfeng Bao. Demonstration of E7766, a novel STING agonist, as a potent immunotherapy in BCG-insensitive non-muscle invasive bladder cancer models via intravesical administration [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 592.