The ATR inhibitor ceralasertib potentiates cancer checkpoint immunotherapy by regulating the tumor microenvironment.
- Resource Type
- Academic Journal
- Authors
- Hardaker EL; Oncology R&D, AstraZeneca, Cambridge, UK.; Sanseviero E; Oncology R&D, AstraZeneca, Gaithersburg, MD, 20878, USA.; Karmokar A; Oncology R&D, AstraZeneca, Cambridge, UK.; Taylor D; Oncology R&D, AstraZeneca, Gaithersburg, MD, 20878, USA.; Milo M; Oncology R&D, AstraZeneca, Cambridge, UK.; Michaloglou C; Oncology R&D, AstraZeneca, Cambridge, UK.; Hughes A; Oncology R&D, AstraZeneca, Cambridge, UK.; Mai M; Oncology R&D, AstraZeneca, Gaithersburg, MD, 20878, USA.; King M; Oncology R&D, AstraZeneca, Cambridge, UK.; Solanki A; Oncology R&D, AstraZeneca, Cambridge, UK.; Magiera L; Oncology R&D, AstraZeneca, Cambridge, UK.; Miragaia R; Oncology R&D, AstraZeneca, Cambridge, UK.; Kar G; Oncology R&D, AstraZeneca, Cambridge, UK.; Standifer N; Oncology R&D, AstraZeneca, Gaithersburg, MD, 20878, USA.; Tempest Therapeutics, Brisbane, CA, USA.; Surace M; Oncology R&D, AstraZeneca, Gaithersburg, MD, 20878, USA.; Gill S; Oncology R&D, AstraZeneca, Cambridge, UK.; Peter A; Oncology R&D, AstraZeneca, Cambridge, UK.; Talbot S; Oncology R&D, AstraZeneca, Cambridge, UK.; Tohumeken S; Oncology R&D, AstraZeneca, Gaithersburg, MD, 20878, USA.; Fryer H; Oncology R&D, AstraZeneca, Gaithersburg, MD, 20878, USA.; Mostafa A; Oncology R&D, AstraZeneca, Gaithersburg, MD, 20878, USA.; Mulgrew K; Oncology R&D, AstraZeneca, Gaithersburg, MD, 20878, USA.; Lam C; Oncology R&D, AstraZeneca, Cambridge, UK.; Hoffmann S; Imaging and Data Analytics, AstraZeneca, Cambridge, UK.; Sutton D; Imaging and Data Analytics, AstraZeneca, Cambridge, UK.; Carnevalli L; Oncology R&D, AstraZeneca, Cambridge, UK.; Calero-Nieto FJ; Oncology R&D, AstraZeneca, Cambridge, UK.; Jones GN; Oncology R&D, AstraZeneca, Cambridge, UK.; Pierce AJ; Oncology R&D, AstraZeneca, Cambridge, UK.; Crescendo Biologics Limited, Cambridge, UK.; Wilson Z; Oncology R&D, AstraZeneca, Cambridge, UK.; Campbell D; Oncology R&D, AstraZeneca, Gaithersburg, MD, 20878, USA.; Nyoni L; Oncology R&D, AstraZeneca, Cambridge, UK.; Martins CP; Oncology R&D, AstraZeneca, Cambridge, UK.; Baker T; CPSS AST, AstraZeneca, Cambridge, UK.; Serrano de Almeida G; CPSS AST, AstraZeneca, Cambridge, UK.; Ramlaoui Z; Oncology R&D, AstraZeneca, Gaithersburg, MD, 20878, USA.; Bidar A; CPSS, Imaging, AstraZeneca, Gothenburg, Sweden.; Phillips B; Data Sciences & Quantitative Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK.; Boland J; Oncology R&D, AstraZeneca, Gaithersburg, MD, 20878, USA.; Iyer S; Oncology R&D, AstraZeneca, Boston, MA, USA.; Barrett JC; Oncology R&D, AstraZeneca, Gaithersburg, MD, 20878, USA.; Loembé AB; Early Clinical Development, AstraZeneca, Oss, the Netherlands.; Fuchs SY; Department of Biomedical Sciences, School of Veterinary Medicine University of Pennsylvania, Philadelphia, PA, 19104, USA.; Duvvuri U; UPMC Department of Otolaryngology and UPMC Hillman Cancer Center, 200 Lothrop St. Suite 500, Pittsburg, PA, 15213, USA.; Lou PJ; National Taiwan University Hospital, No. 7, Chung Shan S. Rd. (Zhongshan S. Rd.), Zhongzheng Dist., Taipei City, 10002, Taiwan.; Nance MA; VA Pittsburgh Healthcare System, University Drive C, Pittsburg, PA, 15240, USA.; Gomez Roca CA; Institut Claudius Regaud-Cancer Comprehensive Center, 1 Avenue Irene Joliot-Curie, IUCT-O, Toulouse, 31059 Cedex 9, France.; Cadogan E; Oncology R&D, AstraZeneca, Cambridge, UK.; Critichlow SE; Oncology R&D, AstraZeneca, Cambridge, UK.; Fawell S; Oncology R&D, AstraZeneca, Boston, MA, USA.; Cobbold M; Oncology R&D, AstraZeneca, Gaithersburg, MD, 20878, USA.; Dean E; Oncology R&D, AstraZeneca, Cambridge, UK.; Valge-Archer V; Oncology R&D, AstraZeneca, Cambridge, UK.; Lau A; Oncology R&D, AstraZeneca, Cambridge, UK.; Gabrilovich DI; Oncology R&D, AstraZeneca, Gaithersburg, MD, 20878, USA. dmitry.gabrilovich@astrazeneca.com.; Barry ST; Oncology R&D, AstraZeneca, Cambridge, UK. simon.t.barry@astrazeneca.com.
- Source
- Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
- Subject
- Language
- English
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.
(© 2024. The Author(s).)