Abstract B006: Ceralasertib enhance efficacy of anti-PDL1 treatment by modulating the tumor microenvironment in a IFNAR I dependent manner.

Abstract This study is aimed to investigate the effect of ATR inhibitor (ATRi) ceralasertib on tumor microenvironment (TME). Ceralasertib has demonstrated encouraging clinical benefits in patients with non-small cell lung cancer who were resistant to PD1/PDL1 treatment. Using different pre-clinical mouse tumor models, we found that antitumor effect of ceralasertib was dependent on CD8 T cells. In fact, depletion of CD8 cells abrogated therapeutic effect of the ATRi. Ceralasertib treatment caused pleotropic effect in TME. It improved the function of T cells, depleted tumor associated macrophages and monocytic myeloid-derived-suppressor cells (MDSC) and inactivated suppressive activity of PMN-MDSC. Ceralasertib treatment resulted in activation of dendritic cells (DC) in tumor-bearing mice. DCs demonstrated increased ability to stimulate T cells, that resulted in enhanced antigen-specific T cell responses in mice treated with ceralasertib in combination with anti-PDL1. Gene expression profile showed significant up-regulation of type I interferon (IFN1) pathway in mice and patients treated with ceralasertib. Using BM chimera mice reconstituted with IFANR1KO for or IFNAR1SA bone marrow we demonstrated a cancelation of antitumor effect, or an enhancement of antitumor effect respectively induced by ceralasertib or combination therapy. DC cells isolated from IFNAR1KO mice treated with Ceralasertib failed to show an activated phenotype and to increase T cell activation demonstrating the pivotal role of type I IFN in ceralasertib-mediated immune activation. In conclusion, our finding showed that ATR inhibitor ceralasertib has a second mechanism of action necessary for its efficacy: modulating the tumor immune microenvironment and increasing sensitivity to anti-PDL1 treatment. Citation Format: Emilio Sanseviero, Devon Taylor, Sehmus Tohumeken, Mimi Mai, Ali Mostafa, Marta Milo, Kathy Mulgrew, Serge Fuchs, Alan Lau, Simon Barry, Mark Cobbold, Dmitry Gabrilovich. Ceralasertib enhance efficacy of anti-PDL1 treatment by modulating the tumor microenvironment in a IFNAR I dependent manner [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B006.