Abstract 4938: OX40 agonist antibody-based combination therapy with PI3Kβ selective inhibitor enhances T cell immunity
Authors: Peng Weiyi , Xu Chunyu , Melendez Brenda , Jackson Heather , McKenzi Jodi A. , Williams Leila J. , Chen Yuan , Mbofung Rina M. , Leahey Sara E. Leahey E. , Lizee Greg , Davies Michael A. , Yanamandra Niranjan , Hwu Patrick 
Published: August 2018

Abstract
OX40 (CD134), a tumor necrosis factor (TNF) receptor family member, plays a critical role in initiating signaling cascades required for full activation of tumor-reactive T cells. Due to its distinct mechanism of action, the use of OX40 agonist-based combinations is emerging as a novel avenue to improve the effectiveness of cancer treatments. Our recently published studies demonstrate that oncogenic activation of the PI3K pathway by loss of the expression of tumor suppressor PTEN, imposes an immunosuppressive microenvironment in favor of tumor immune evasion. These results highlight the therapeutic potential of combinational therapy using OX40 agonists and PI3K inhibitors in cancer patients. In this study, we sought to evaluate the antitumor efficacy of the combination of an OX40 agonist antibody and a PI3Kβ selective inhibitor, GSK2636771, in tumors with PTEN loss. By using a genetically engineered mouse (GEM) model of melanoma, which can spontaneously develop tumors with PTEN loss, we observed that combination therapy using anti-OX40 and GSK2636771 significantly delayed tumor growth and improved survival time of mice bearing PTEN loss tumors. This combinational treatment was also well tolerated in experimental mice. Unlike the combination of GSK2636771 and immune checkpoint blockers, this combinational treatment did not result in an increase in the number of CD8+ tumor-infiltrating T cells, but significantly enhanced the percentage of Ki67+ CD8+ T cells at the tumor site when compared to either treatment alone. These results suggest that GSK2636771 treatment can synergize with OX40 agonists to augment effector functions of tumor-reactive T cells. To further confirm this synergistic effect, we measured serum levels of 45 cytokines/chemokines in tumor-bearing mice receiving anti-OX40 alone or in combination with GSK2636771. Serum levels of CCL4, CXCL10 and IFN-γ, which are mainly produced by memory and/or effector T cells, were significantly increased in mice in the combination cohort in comparison to the monotherapy cohorts. More importantly, using a vaccine mouse model, we demonstrate that GSK2636771 in combination with anti-OX40 did not significantly impair the generation and maintenance of memory T cells. Taken together, our results suggest that the combinational approach of an OX40 agonist antibody and GSK2636771 may induce robust and durable antitumor T cell immunity. Our study also provides a rationale to explore the clinical activity of an OX40 agonist antibody in combination with GSK2636771 in cancer patients with PTEN loss tumors.
Citation Format: Weiyi Peng, Chunyu Xu, Brenda Melendez, Heather Jackson, Jodi A. McKenzi, Leila J. Williams, Yuan Chen, Rina M. Mbofung, Sara E. Leahey E. Leahey, Greg Lizee, Michael A. Davies, Niranjan Yanamandra, Patrick Hwu. OX40 agonist antibody-based combination therapy with PI3Kβ selective inhibitor enhances T cell immunity [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 4938.