The ATR inhibitor ceralasertib potentiates cancer checkpoint immunotherapy by regulating the tumor microenvironment.
Journal
Nature communications
Journal Volume
15
Journal Issue
1
Start Page
Article number 1700
ISSN
2041-1723
Date Issued
2024-02-24
Author(s)
Hardaker, Elizabeth L
Sanseviero, Emilio
Karmokar, Ankur
Taylor, Devon
Milo, Marta
Michaloglou, Chrysis
Hughes, Adina
Mai, Mimi
King, Matthew
Solanki, Anisha
Magiera, Lukasz
Miragaia, Ricardo
Kar, Gozde
Standifer, Nathan
Surace, Michael
Gill, Shaan
Peter, Alison
Talbot, Sara
Tohumeken, Sehmus
Fryer, Henderson
Mostafa, Ali
Mulgrew, Kathy
Lam, Carolyn
Hoffmann, Scott
Sutton, Daniel
Carnevalli, Larissa
Calero-Nieto, Fernando J
Jones, Gemma N
Pierce, Andrew J
Wilson, Zena
Campbell, David
Nyoni, Lynet
Martins, Carla P
Baker, Tamara
Serrano de Almeida, Gilberto
Ramlaoui, Zainab
Bidar, Abdel
Phillips, Benjamin
Boland, Joseph
Iyer, Sonia
Barrett, J Carl
Loembé, Arsene-Bienvenu
Fuchs, Serge Y
Duvvuri, Umamaheswar
Nance, Melonie A
Gomez Roca, Carlos Alberto
Cadogan, Elaine
Critichlow, Susan E
Fawell, Steven
Cobbold, Mark
Dean, Emma
Valge-Archer, Viia
Lau, Alan
Gabrilovich, Dmitry I
Barry, Simon T
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.
Type
journal article