Abstract 2338: The GLS1 inhibitor IPN60090 enhances antitumor immune response through metabolic reprogramming of T cells and impacts on the tumor microenvironment
Authors: Suzuki Erika , Molina Jennifer , Spencer Nakia D. , Bristow Christopher A. , Harris Angela L. , Feng Ningping , Mahendra Mikhila , Gera Sonal , Soth Michael J. , Le Kang , Yap Timothy A. , Draetta Giulio , Jones Philip , Heffernan Timothy P. , Kovacs Jeffrey J. 
Published: July 2021

Abstract
Therapeutic agents targeting metabolism in the tumor microenvironment have been of increasing interest in recent years, however, the complexities of the interplay between tumor, stromal and immune cell interactions add complexity to these therapeutic approaches. We have previously disclosed the development of the GLS1 inhibitor, IPN60090, which is currently progressing through Phase 1 studies (NCT03894540) in multiple indication-specific biomarker-positive patient populations. In order to fully appreciate the opportunity to enhance IPN60090 activity in patients, we explored the impact of GLS1 inhibition on the activity of the immune system. Glutamine metabolism has been shown to play important and varied roles within the immune compartment including, but not limited to, roles in T-cell activation, T-cell effector functions and progression of exhaustion phenotypes. During T-cell activation, glutamine is utilized to drive activated T-cells towards a glycolytic phenotype. Eventually, activated T-cells exhaust and shift away from glycolysis towards fatty acid oxidation. Interestingly, it has been reported that the interaction of PD1 with PD-L1 blocks glutamine import and decreases glycolysis. Given these data, we hypothesized that inhibition of GLS1 with IPN60090 might enhance checkpoint blockade by increasing levels of glutamine in the tumor microenvironment, thus enhancing anti-tumor immune responses. In ex vivo culture systems, we show that IPN60090-mediated GLS1 inhibition increases the glycolytic activity of CD4+ and CD8+ T-cells, suggesting that GLS1 inhibition allows cells to maintain an energetically favorable phenotype. Furthermore, we show that IPN60090 enhances checkpoint blockade through cooperation with αPD1 therapy in two syngeneic mouse models which do not harbor predictive biomarkers of response to IPN60090 and which are refractory to checkpoint blockade. The observed synergy is due in part to IPN60090-dependent depletion of regulatory T-cells (Treg) and a concurrent increase in the CD8+ T-cell to Treg ratio in the tumor microenvironment. These data suggest that IPN60090 may show clinical benefit by enhancing immune response in the context of checkpoint blockade and have served as the justification for phase 1b trials in combination with Pembrolizumab which will enroll in 2021.
Citation Format: Erika Suzuki, Jennifer Molina, Nakia D. Spencer, Christopher A. Bristow, Angela L. Harris, Ningping Feng, Mikhila Mahendra, Sonal Gera, Michael J. Soth, Kang Le, Timothy A. Yap, Giulio Draetta, Philip Jones, Timothy P. Heffernan, Jeffrey J. Kovacs. The GLS1 inhibitor IPN60090 enhances antitumor immune response through metabolic reprogramming of T cells and impacts on the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2338.