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

• Published in: Nature communications Vol. 15; no. 1; p. 1700
• Main Authors: 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, Lou, Pei-Jen, 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.02.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/106; 13/31; 13/51; 14/63; 631/250/580; 631/67/1059; 64/60; 692/4028/67/327; Animal models; Animals; Antibodies; Anticancer properties; Antitumor activity; Antitumor agents; Ataxia; Ataxia telangiectasia; Ataxia Telangiectasia Mutated Proteins; B7-H1 Antigen; Cancer; CD8 antigen; CD8-Positive T-Lymphocytes; Cell culture; Cell Line, Tumor; Disease Models, Animal; Humanities and Social Sciences; Humans; Immune checkpoint inhibitors; Immunomodulation; Immunotherapy; Indoles; Inhibitors; Interferon; Lung cancer; Lymphocytes T; Melanoma; Mice; Morpholines; multidisciplinary; Myeloid cells; Neoplasms; Patients; PD-L1 protein; Pyrimidines; Science; Science (multidisciplinary); Sulfonamides; Tumor cells; Tumor Microenvironment; Tumors; Up-regulation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-45996-4

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. The ATR inhibitor ceralasertib has shown clinical activity in combination with immune-checkpoint inhibitors in several cancer types. Here the authors report the anti-tumor activity and the immunomodulatory changes, dependent on up-regulation of type I interferon pathway, following intermittent ATR inhibition in preclinical cancer models.