Abstract 1664: Inhibition of arginase in combination with radiation therapy shows increased immune-activation and anti-tumor activity in syngeneic tumor models

Abstract

Abstract The tumor microenvironment (TME) has multiple mechanisms of immune-suppression including recruitment of arginase (ARG) expressing myeloid cells. ARG is an enzyme that catalyzes hydrolysis of L-arginine into urea and L-ornithine. Given L-arginine is essential for optimal function of both T cells and natural killer (NK) cells, inhibition of ARG has been recognized as a potential therapeutic approach to reverse immune-suppression and optimize anti-tumor immunity. We recently presented development of a novel ARG inhibitor, AZD0011, and demonstrated immune activation and anti-tumor activity as single agent and in combination with a-PD-L1 in various tumor models. We now expand these findings demonstrating combination benefit with radiation therapy. Radiation therapy (5 gray on day 6 and 9 after tumor cell implant) demonstrated an increase of both the number of arginase expressing myeloid cells, and NK cells in the TME of Lewis Lung (LL) tumors. Immuno-histochemistry also demonstrated a redistribution of the location of ARG positive myeloid cells with a marked increase at the edge of the tumor. LL tumor bearing mice receiving either AZD0011 (30 mg/kg twice daily), or radiation therapy as monotherapy did not show a significant anti-tumor response reaching 0.3% and 28% tumor growth inhibition (TGI) respectively (p>0.05 versus vehicle). In contrast, combination treatment showed a marked increased efficacy averaging 60% TGI (p<0.05 versus either monotherapy). Combination treatment also further increased several markers of immune activation including a doubling of the number of IL2+ or IFNg+ CD4+ and CD8+ T-cells in tumor draining lymph nodes. In summary, our pre-clinical data demonstrates that radiation therapy increases the number and location of intra-tumoral ARG expression myeloid cells and increased anti-tumor activity when combining the ARG inhibitor AZD0011 with radiation therapy. Citation Format: Alwin Schuller, Aatman Doshi, Susan Cantin, Matt Griffin, Maryann San Martin, Theresa Proia, Corinne Reimer, Scott Mlynarski, Ray Finlay, Wenlin Shao. Inhibition of arginase in combination with radiation therapy shows increased immune-activation and anti-tumor activity in syngeneic tumor models [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 1664.