دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: The ATR inhibitor ceralasertib potentiates cancer checkpoint immunotherapy by regulating the tumor microenvironment.
المؤلفون: 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.
المصدر: Nature communications [Nat Commun] 2024 Feb 24; Vol. 15 (1), pp. 1700. Date of Electronic Publication: 2024 Feb 24.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: 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
أسماء مطبوعة: Original Publication: [London] : Nature Pub. Group
مواضيع طبية MeSH: CD8-Positive T-Lymphocytes* , Neoplasms* , Indoles* , Morpholines* , Pyrimidines* , Sulfonamides*, Humans ; Animals ; Mice ; B7-H1 Antigen ; Tumor Microenvironment ; Cell Line, Tumor ; Immunotherapy ; Disease Models, Animal ; Ataxia Telangiectasia Mutated Proteins
مستخلص: 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).)
References: Oncogene. 2020 Jun;39(25):4869-4883. (PMID: 32444694)
Cell Rep. 2019 Jul 2;28(1):245-256.e4. (PMID: 31269444)
Nat Cancer. 2022 Jul;3(7):808-820. (PMID: 35637402)
EMBO J. 2003 Oct 15;22(20):5480-90. (PMID: 14532120)
Cancer Discov. 2019 May;9(5):646-661. (PMID: 30777870)
JCI Insight. 2023 Feb 22;8(4):. (PMID: 36810257)
Oncoimmunology. 2022 Jun 18;11(1):2083755. (PMID: 35756843)
Bioinformatics. 2010 Jan 1;26(1):139-40. (PMID: 19910308)
Cytometry A. 2015 Jul;87(7):636-45. (PMID: 25573116)
Clin Cancer Res. 2019 Jun 1;25(11):3392-3403. (PMID: 30770349)
Cancer Discov. 2019 Jun;9(6):722-737. (PMID: 31015319)
Ann Oncol. 2022 Feb;33(2):193-203. (PMID: 34710570)
Methods Mol Biol. 2021;2236:19-28. (PMID: 33237537)
Sci Transl Med. 2021 Oct 27;13(617):eabe6201. (PMID: 34705519)
Cell Syst. 2018 May 23;6(5):612-620.e5. (PMID: 29605184)
Database (Oxford). 2011 Nov 13;2011:bar049. (PMID: 22083790)
J Clin Invest. 2018 Aug 31;128(9):3926-3940. (PMID: 29952768)
J Immunother Cancer. 2022 Jul;10(7):. (PMID: 35790315)
Nat Commun. 2021 Mar 19;12(1):1717. (PMID: 33741967)
J Immunother Cancer. 2020 May;8(1):. (PMID: 32461345)
Nat Rev Immunol. 2021 Aug;21(8):485-498. (PMID: 33526920)
J Natl Cancer Inst. 2016 Oct 5;109(1):. (PMID: 27707838)
J Biol Chem. 2004 Nov 5;279(45):46614-20. (PMID: 15337770)
Cancer Res. 2022 Mar 15;82(6):1140-1152. (PMID: 35078817)
J Immunol. 2020 Apr 15;204(8):2192-2202. (PMID: 32152071)
Cancer Res. 2019 Jul 15;79(14):3762-3775. (PMID: 31123088)
Cancer Inform. 2014 Dec 09;13(Suppl 4):65-72. (PMID: 25574127)
Nat Protoc. 2018 Oct;13(10):2121-2148. (PMID: 30258176)
Curr Opin Immunol. 2017 Apr;45:43-51. (PMID: 28192720)
Am J Cancer Res. 2018 Jul 01;8(7):1307-1316. (PMID: 30094103)
EMBO Mol Med. 2014 Mar;6(3):384-97. (PMID: 24480543)
Cell Rep. 2022 Sep 20;40(12):111371. (PMID: 36130512)
Nat Commun. 2020 Sep 29;11(1):4903. (PMID: 32994412)
Nat Med. 2024 Feb 13;:. (PMID: 38351187)
EMBO J. 2020 Jul 15;39(14):e104036. (PMID: 32484965)
Nat Commun. 2017 Nov 24;8(1):1751. (PMID: 29170499)
J Med Chem. 2018 Nov 21;61(22):9889-9907. (PMID: 30346772)
Nat Commun. 2017 Dec 14;8(1):2122. (PMID: 29242535)
Oncoimmunology. 2022 Sep 13;11(1):2117321. (PMID: 36117525)
Pharmacol Ther. 2018 Aug;188:155-167. (PMID: 29580942)
المشرفين على المادة: 85RE35306Z (ceralasertib)
0 (B7-H1 Antigen)
EC 2.7.11.1 (ATR protein, human)
EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins)
0 (Indoles)
0 (Morpholines)
0 (Pyrimidines)
0 (Sulfonamides)
تواريخ الأحداث: Date Created: 20240224 Date Completed: 20240226 Latest Revision: 20240227
رمز التحديث: 20240227
مُعرف محوري في PubMed: PMC10894296
DOI: 10.1038/s41467-024-45996-4
PMID: 38402224
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-1723
DOI:10.1038/s41467-024-45996-4