Abstract 4843: TP53-stabilization with APR-246 enhances antitumor effects of immune checkpoint blockade in preclinical models

Abstract

Abstract An emerging body of literature suggests a role of TP53 pathway in antitumor immunity including antigen presentation and T cell proliferation. Stabilization of TP53 could therefore alter the immune tumor microenvironment, enabling the immune system to target tumor cells more effectively. APR-246 covalently modifies the core domain of cellular TP53 through the alkylation of thiol groups, leading to reactivation of endogenous TP53 activity. To further study the effect of APR-246 on antitumor immunity we used a B16 pre-clinical melanoma mouse model. In vitro treatment of B16 cells with APR-246 caused intracellular accumulation of TP53, leading to increased apoptosis. However, treatment of B16-melanoma bearing mice with APR-246 monotherapy did not result in a statistically significant change in tumor growth or survival. Analyses of the tumor immune microenvironment showed increased immune potentiating M1 polarized tumor-associated macrophages, and Granzyme B activity in CD8+ T cells, suggesting enhanced anti-tumor immunity. Concomitantly, there was increased PD-L1 expression in the macrophages, PD-1 expression on CD8+ T cells, and Foxp3+ Tregs in tumors from APR-246 treated animals. Therefore, we decided to combine anti-PD-1 antibody (RMP-1) to APR-246 treatment in tumor-bearing mice. The combination led to a significant delay in tumor growth (P < 0.001) and improved survival of B16-bearing mice compared to anti-PD1 or APR-246 monotherapies (P < 0.01). Improved responses were also seen in MC38 colorectal cancer-bearing mice (P < 0.01). The anti-tumor effects of APR-246 and anti-PD1 were T cell dependent and abrogated in hosts lacking T cells. Analyses of the tumor immune microenvironment showed that the combination decreases proliferation but increases cytolytic activity of CD8+ T cells compared to anti-PD1 alone. We next studied the effect of combining APR-246 with anti-PD1+ anti-CTLA-4 (9B9). Combination of APR-246 with dual immune checkpoint blockade using anti-PD1 and anti-CTLA-4 showed further tumor growth inhibition in B16-melanoma compared to monotherapies (P < 0.001). Our studies support a role for restoring TP53 in the tumor microenvironment and provide evidence that reactivation of TP53 by APR-246 can enhance anti-tumor immune responses and inhibit tumor growth in preclinical models. Citation Format: Arnab Ghosh, Judith Michel, Lauren Dong, Nathan Suek, Hong Zhong, Sadna Budhu, Olivier de Henau, Jedd Wolchok, Taha Merghoub. TP53-stabilization with APR-246 enhances antitumor effects of immune checkpoint blockade in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4843.