Abstract 1852: Systemic delivery of ST317, a cell penetrating STING pathway sensitizer, results in strong anti-tumor activity

Abstract

Abstract Pharmacological activation of the STING pathway is being assessed as a strategy to stimulate both the innate and adaptive arms of the immune system to trigger an anti-tumor immune response in so-called "cold" tumors. Although the first generation of STING agonists dosed intratumorally showed a strong anti-tumor response in preclinical models, positive clinical data has so far been limited, potentially due to reduced efficacy in non-injected tumors. Newer classes of STING agonists that are delivered systemically are expected to deliver more consistent and predictable levels of STING activation, but may less tolerated due to untargeted activation of the immune system resulting in immune related adverse events. We have previously demonstrated that IFI16 promotes activation of the cGAMP-activated STING pathway by a process relying on IFI16 PYRIN domain-dependent protein-protein interactions1. Based on these findings, an IFI16 Pyrin domain-derived peptide incorporating a cell penetrating peptide that recapitulates the agonist-dependent activation of the STING pathway by IFI16, was developed. This peptide, ST317, acts as a STING sensitizer for effective and safe induction of anti-tumour immune responses only at sites where STING agonists are present. In vitro, ST317 sensitizes STING to pathway activators (Cytoplasmic DNA and cGAMP) and pharmacological STING agonists including ADU-S100 and diABZI compound 3, reducing the EC50 values of agonist-induced STING pathway activation while inducing supraphysiological (i.e. increasing the EMax) levels of pro-inflammatory cytokines/chemokines (e.g. Type I interferon and CXCL10) in cell line and primary cells. Mechanistically, ST317 sensitizes STING to cGAMP by accelerating and increasing STING translocation from the endoplasmic reticulum to the Golgi, resulting in earlier and longer activation of the STING pathway components, as determined by the phosphorylation kinetics of TBK1 and IRF3, as well as STING itself. Consistent with its in vitro pharmacological profile, ST317 can be safely administered parenterally without evidence of peripheral STING activation. In vivo experiments in immunocompetent syngeneic mouse models demonstrate that ST317 dosed I.V. was well tolerated and was associated with anti-tumor efficacy when used as a single agent or in combination with immune checkpoint blockers such as anti-PD1. In addition, ST317 improved the anti-tumor response to a pharmacological STING agonist at doses that do not cause immune cell death that result from over-dosing this type of agent. In summary, ST317 represents a new class of STING pathway activator, which enables safe systemic administration while giving rise to enhanced STING pathway activation only at sites at which STING agonists are present. The data presented here warrant the assessment of ST317 in cancer patients in a clinical trial. 1. Jønsson et al. 2017 DOI: 10.1038/ncomms14391 Citation Format: Claus Elsborg Olesen, Esben Axelgaard, Emil Nilsson, Anna H. Hansen, Isis Benoit-Lizon, Justin V. Joseph, Kristina Byskov, Magnus Strandh, Maja Myrcha, Pernille Rimmer Noer, Ulrich Sensfuss, Richard Charles Sainson, Richard C. Bethell, Martin R. Jakobsen. Systemic delivery of ST317, a cell penetrating STING pathway sensitizer, results in strong anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1852.