Abstract 3773: RORγ agonist enhances antitumor effects of agonist anti-OX40 antibody

Abstract

Abstract Combination immunotherapy strategies are being developed to improve the clinical outcome in cancer patients. T-cell costimulation through OX40 has been shown to promote expansion and proliferation of effector T-cells leading to enhanced effector functions, memory generation and immune inflammatory antitumor responses. However, treatment with anti-OX40 as a single agent has not led to major positive clinical outcomes. Therefore, anti-OX40 is an ideal candidate for combination immunotherapy. In preclinical models, we have recently shown that combining anti-PD-1 concurrently with anti-OX40 negates the effects of agonist anti-OX40, making identification of combination partners crucial for antitumor therapy. RORγt, a master transcription factor, is known to drive Type 17 T-cell differentiation. Synthetic, small-molecule RORγ agonists have been shown to enhance Type 17 T-cell effector functions and survival, decrease immune suppressive mechanisms and modulate expression of a number of costimulatory and coinhibitory molecules. We hypothesized that combining RORγ agonist could enhance the antitumor effects of anti-OX40. Using a murine model where vaccine is used to prime the immune system, we assessed the effects of anti-OX40 antibody combined with a RORγ agonist (LYC-54143) on growth of established tumors and survival. We found that the combined treatment resulted in a significantly delayed tumor growth and prolonged mice survival. Analysis of the tumor microenvironment revealed that combination therapy significantly increased the numbers of total CD4+ T-cells including RORγt+ and highly activated INFγ+ cells, decreasing Treg numbers. Moreover, we found that RORγ agonist resulted in an increase in the numbers of total, antigen-specific, granzyme B+, and IFNγ+ CD8+ T-cells in the TME. These results show that inducing Th17 cells within the TME produces better anti-OX40 effect, suggesting that agonist anti-OX40 and RORγ agonist treatment is a novel potent combination for cancer immunotherapy. Citation Format: Pankaj Gaur, Vivek Verma, Rahul Nandre, Pooja Vir, Hua Wang, Baolin Kang, Laura Carter, Xiao Hu, Xikui Liu, Seema Gupta, Samir Khleif. RORγ agonist enhances antitumor effects of agonist anti-OX40 antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3773.