Abstract 3317: Discovery of novel STING agonists with robust anti-tumor activity

Abstract

Abstract Introduction: Stimulator of interferon genes (STING) is an endoplasmic reticulum (ER) membrane signaling protein, which plays a key role in the sensing of cytoplasmic DNA arising from bacterial and viral infection, as well as self-DNA. Several studies have shown that STING signaling is essential for antitumor immunity by inducing the production of type I IFN and activating both innate and adaptive immunity. Therefore, activation of STING pathway in the tumor microenvironment could be a potential effective approach for cancer immunotherapy. Here, we present the characterization of novel STING agonists in a variety of in vitro cell lines and in vivo murine models. Methods: THP-1 monocyte cells and HEK 293-derived cells transfected with STING variants were used for cellular potency evaluation. Multiple murine tumor models were used for evaluation of in vivo efficacy. Tumor cells were inoculated into C57BL/6 mice and compounds were injected intratumorally three times at every three days when tumors reached a mean volume of approximately 100 mm3. Compounds-treated mice free from tumor for 30 days were re-challenged with MC38 tumor cells in MC38 murine model. Results: Several lead compounds CS-1018, CS-1020 and CS-1010 activate mouse and human STING variants in vitro with much better potency than natural ligand cGAMP and reference compound X. CS-1018 demonstrated dose dependent robust antitumor activity in B16F10 and MC38 mouse models. 3 out of 8 mice achieve complete responses at the dose of 100 ug in B16F10, 25% or 75% of mice were tumor free when treated with 5 ug or 25 ug of compound respectively in MC38. The survival mice from 5 ug and 25 ug groups remained tumor-free after re-challenged with another inoculation of MC38 cancer cells. The antitumor activity of compound CS-1020 and CS-1010 was also demonstrated in MC38 mouse model. When CS-1020 was dosed at 5 ug or 25 ug, complete responses were observed in 63% or 88% of mice respectively. In the case of CS-1010, the dose of 5 ug provides complete responses in 100% of treated mice. Similarly, both compounds induced immune-mediated tumor rejection when re-challenged with the same cancer cells. Conclusions: We have identified several STING agonists, which demonstrated better cellular potency to mouse and human STING alleles compared to natural ligand cGAMP and reference compound. All compounds showed dose dependent antitumor activity in MC38 or B16F10 syngeneic models, in addition, tumor-free mice after treatment of compounds developed tumor specific immunologic memory response in MC38 murine model. Combination studies of identified STING agonists with other IO agents are currently ongoing. The results will be discussed. Citation Format: Anrong Li, Yuntao Song, Chen Dong, Xiaoqi Chen, Junbao Yang. Discovery of novel STING agonists with robust anti-tumor activity [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 3317.