Abstract 2899: PARG inhibition provokes a DNA damage-dependent innate immune reaction that enhances ICI-driven anti-tumor immunity

Abstract Poly (ADP-Ribose) glycohydrolase (PARG) is an emerging oncology drug target with a unique role in the resolution of DNA damage repair and DNA replication fork restart through hydrolysis of Poly (ADP-ribose) (PAR) chains. IDE161 is a potent, orally bioavailable, small molecule that directly binds the active site of PARG to impede PAR chain hydrolysis and exhibits robust anti-tumor activity in preclinical models associated with replication stress. Molecular profiling of baseline cell states across 257 tumor cell lines indicated innate immune signaling was strongly associated with responsiveness to IDE161. Moreover, induction of interferon regulatory factor (IRF) activity was the dominant gene regulation program detected in tumors in response to IDE161 exposure in vivo. Given the body of evidence indicating replication stress can lead to a type 1 interferon response via nucleic acid sensing, we speculated that IDE161-induced innate immune signaling is a consequence of cytosolic exposure to DNA repair intermediates including RNA: DNA heteroduplexes produced by failed resolution of stalled DNA replication forks. Consistent with this, IDE161-dependent cancer cell death was preceded by transcription-replication conflicts, replication catastrophe, innate immune pathway activation, and IFN-β production and secretion. To evaluate the potential for innate immune priming of an adaptive immune reaction, IDE161/immune checkpoint inhibitor (ICI) combination activity was assessed in a syngeneic mouse tumor model reported to be partially responsive to PARG inhibition. The combination of IDE161 with RPM1-14, an antibody directed against the mouse-programmed cell death protein 1 (PD-1) receptor, showed greater anti-tumor activity than either agent alone and altered the frequency of tumor-infiltrating lymphocytes towards an immune-activated phenotype. Moreover, T-cell receptor sequencing of clinical PBMC specimens from IDE161 monotherapy patients revealed clonal expansion in the T-cell receptor repertoires on treatment as compared to baseline. These cumulative observations suggest that IDE161 can induce an innate-immune-pathway-mediated priming of an antitumor adaptive immune response, and thus may deliver both tumor autonomous and nonautonomous therapeutic benefits. This relationship is currently under evaluation with IDE161/pembrolizumab combination therapy In patients with advanced endometrial cancer who have previously progressed on anti-PD-1 therapy (NCT05787587) Citation Format: Reeja Maskey, Megan Conway, Pei Xin Lim, Amber C. Donahue, Emily Fitz, Vidhya Nagarajan, Arjun A. Rao, Zabrisky Roland, Natalie Bresnahan, David Trinh, Ivan Shabalin, Kelly Trego, Jonathon Ryan, Rebeca M. Choy, Peter Teriete, Christian Frey, Yuchen Bai, Paul A. Barsanti, Claire Neilan, Mike White, Diana M. Munoz. PARG inhibition provokes a DNA damage-dependent innate immune reaction that enhances ICI-driven anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2899.