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The ATR inhibitor ceralasertib potentiates cancer checkpoint immunotherapy by regulating the tumor microenvironment

Author

Listed:
  • Elizabeth L. Hardaker

    (Oncology R&D, AstraZeneca)

  • Emilio Sanseviero

    (Oncology R&D, AstraZeneca)

  • Ankur Karmokar

    (Oncology R&D, AstraZeneca)

  • Devon Taylor

    (Oncology R&D, AstraZeneca)

  • Marta Milo

    (Oncology R&D, AstraZeneca)

  • Chrysis Michaloglou

    (Oncology R&D, AstraZeneca)

  • Adina Hughes

    (Oncology R&D, AstraZeneca)

  • Mimi Mai

    (Oncology R&D, AstraZeneca)

  • Matthew King

    (Oncology R&D, AstraZeneca)

  • Anisha Solanki

    (Oncology R&D, AstraZeneca)

  • Lukasz Magiera

    (Oncology R&D, AstraZeneca)

  • Ricardo Miragaia

    (Oncology R&D, AstraZeneca)

  • Gozde Kar

    (Oncology R&D, AstraZeneca)

  • Nathan Standifer

    (Oncology R&D, AstraZeneca
    Tempest Therapeutics)

  • Michael Surace

    (Oncology R&D, AstraZeneca)

  • Shaan Gill

    (Oncology R&D, AstraZeneca)

  • Alison Peter

    (Oncology R&D, AstraZeneca)

  • Sara Talbot

    (Oncology R&D, AstraZeneca)

  • Sehmus Tohumeken

    (Oncology R&D, AstraZeneca)

  • Henderson Fryer

    (Oncology R&D, AstraZeneca)

  • Ali Mostafa

    (Oncology R&D, AstraZeneca)

  • Kathy Mulgrew

    (Oncology R&D, AstraZeneca)

  • Carolyn Lam

    (Oncology R&D, AstraZeneca)

  • Scott Hoffmann

    (Imaging and Data Analytics, AstraZeneca)

  • Daniel Sutton

    (Imaging and Data Analytics, AstraZeneca)

  • Larissa Carnevalli

    (Oncology R&D, AstraZeneca)

  • Fernando J. Calero-Nieto

    (Oncology R&D, AstraZeneca)

  • Gemma N. Jones

    (Oncology R&D, AstraZeneca)

  • Andrew J. Pierce

    (Oncology R&D, AstraZeneca
    Crescendo Biologics Limited)

  • Zena Wilson

    (Oncology R&D, AstraZeneca)

  • David Campbell

    (Oncology R&D, AstraZeneca)

  • Lynet Nyoni

    (Oncology R&D, AstraZeneca)

  • Carla P. Martins

    (Oncology R&D, AstraZeneca)

  • Tamara Baker

    (CPSS AST, AstraZeneca)

  • Gilberto Serrano de Almeida

    (CPSS AST, AstraZeneca)

  • Zainab Ramlaoui

    (Oncology R&D, AstraZeneca)

  • Abdel Bidar

    (CPSS, Imaging, AstraZeneca)

  • Benjamin Phillips

    (Discovery Sciences, R&D, AstraZeneca)

  • Joseph Boland

    (Oncology R&D, AstraZeneca)

  • Sonia Iyer

    (Oncology R&D, AstraZeneca)

  • J. Carl Barrett

    (Oncology R&D, AstraZeneca)

  • Arsene-Bienvenu Loembé

    (Early Clinical Development, AstraZeneca)

  • Serge Y. Fuchs

    (School of Veterinary Medicine University of Pennsylvania)

  • Umamaheswar Duvvuri

    (UPMC Department of Otolaryngology and UPMC Hillman Cancer Center)

  • Pei-Jen Lou

    (National Taiwan University Hospital)

  • Melonie A. Nance

    (University Drive C)

  • Carlos Alberto Gomez Roca

    (1 Avenue Irene Joliot-Curie, IUCT-O)

  • Elaine Cadogan

    (Oncology R&D, AstraZeneca)

  • Susan E. Critichlow

    (Oncology R&D, AstraZeneca)

  • Steven Fawell

    (Oncology R&D, AstraZeneca)

  • Mark Cobbold

    (Oncology R&D, AstraZeneca)

  • Emma Dean

    (Oncology R&D, AstraZeneca)

  • Viia Valge-Archer

    (Oncology R&D, AstraZeneca)

  • Alan Lau

    (Oncology R&D, AstraZeneca)

  • Dmitry I. Gabrilovich

    (Oncology R&D, AstraZeneca)

  • Simon T. Barry

    (Oncology R&D, AstraZeneca)

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.

Suggested Citation

  • Elizabeth L. Hardaker & Emilio Sanseviero & Ankur Karmokar & Devon Taylor & Marta Milo & Chrysis Michaloglou & Adina Hughes & Mimi Mai & Matthew King & Anisha Solanki & Lukasz Magiera & Ricardo Miraga, 2024. "The ATR inhibitor ceralasertib potentiates cancer checkpoint immunotherapy by regulating the tumor microenvironment," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45996-4
    DOI: 10.1038/s41467-024-45996-4
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    References listed on IDEAS

    as
    1. Filippo Veglia & Vladimir A. Tyurin & Dariush Mohammadyani & Maria Blasi & Elizabeth K. Duperret & Laxminarasimha Donthireddy & Ayumi Hashimoto & Alexandr Kapralov & Andrew Amoscato & Roberto Angelini, 2017. "Lipid bodies containing oxidatively truncated lipids block antigen cross-presentation by dendritic cells in cancer," Nature Communications, Nature, vol. 8(1), pages 1-16, December.
    2. Anders Lundin & Michelle J. Porritt & Himjyot Jaiswal & Frank Seeliger & Camilla Johansson & Abdel Wahad Bidar & Lukas Badertscher & Sandra Wimberger & Emma J. Davies & Elizabeth Hardaker & Carla P. M, 2020. "Development of an ObLiGaRe Doxycycline Inducible Cas9 system for pre-clinical cancer drug discovery," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    3. Hiro Sato & Atsuko Niimi & Takaaki Yasuhara & Tiara Bunga Mayang Permata & Yoshihiko Hagiwara & Mayu Isono & Endang Nuryadi & Ryota Sekine & Takahiro Oike & Sangeeta Kakoti & Yuya Yoshimoto & Kathryn , 2017. "DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    4. Kevin Alicea-Torres & Emilio Sanseviero & Jun Gui & Jinyun Chen & Filippo Veglia & Qiujin Yu & Laxminarasimha Donthireddy & Andrew Kossenkov & Cindy Lin & Shuyu Fu & Charles Mulligan & Brian Nam & Gre, 2021. "Immune suppressive activity of myeloid-derived suppressor cells in cancer requires inactivation of the type I interferon pathway," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
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