The ATR inhibitor ceralasertib potentiates cancer checkpoint immunotherapy by regulating the tumor microenvironment
Elizabeth Hardaker, Emilio Sanseviero, Ankur Karmokar, Devon K. Taylor, Marta Milo, Chrysis Michaloglou, Adina Hughes, Mimi Mai, Matthew King, Anisha Solanki, Łukasz Magiera, Ricardo J. Miragaia, Gozde Kar, Nathan Standifer, Michael Surace, Shaan Gill, Alison Peter, Sara Talbot, Şehmus Tohumeken, Henderson Fryer, Mostafa Ali, Kathy Mulgrew, Carolyn S.P. Lam, Scott Hoffmann, Daniel Sutton, Larissa S. Carnevalli, Fernando J. Calero‐Nieto, Gemma N. Jones, Andrew J. Pierce, Zena Wilson, David G. Campbell, Lynet Nyoni, Carla P. Martins, Tamara Baker, Gilberto S. Almeida, Zainab Ramlaoui, Abdel Wahad Bidar, Benjamin Phillips, Joseph F. Boland, Sonia Iyer, J. Carl Barrett, Arsène‐Bienvenu Loembé, Serge Y. Fuchs, Umamaheswar Duvvuri, Pei‐Jen Lou, Melonie A. Nance, Carlos Gomez‐Roca, Elaine Cadogan, Susan E Critichlow, Steven Fawell, Mark Cobbold, Emma Dean, Viia Valge-Archer, Alan Lau, Dmitry I. Gabrilovich, Simon T. Barry
Abstract
Abstract The Ataxia telangiectasia and Rad3-related (ATR) inhibitor ceralasertib in combination with the PD-L1 antibody durvalumab demonstrated encouraging clinical benefit in melanoma and lung cancer patients who progressed on immunotherapy. Here we show that modelling of intermittent ceralasertib treatment in mouse tumor models reveals CD8 + T-cell dependent antitumor activity, which is separate from the effects on tumor cells. Ceralasertib suppresses proliferating CD8 + T-cells on treatment which is rapidly reversed off-treatment. Ceralasertib causes up-regulation of type I interferon (IFNI) pathway in cancer patients and in tumor-bearing mice. IFNI is experimentally found to be a major mediator of antitumor activity of ceralasertib in combination with PD-L1 antibody. Improvement of T-cell function after ceralasertib treatment is linked to changes in myeloid cells in the tumor microenvironment. IFNI also promotes anti-proliferative effects of ceralasertib on tumor cells. Here, we report that broad immunomodulatory changes following intermittent ATR inhibition underpins the clinical therapeutic benefit and indicates its wider impact on antitumor immunity.