دورية أكاديمية
أعرض في EDS

Epigenetic priming enhances antitumor immunity in platinum-resistant ovarian cancer.

التفاصيل البيبلوغرافية
العنوان: Epigenetic priming enhances antitumor immunity in platinum-resistant ovarian cancer.
المؤلفون: Chen S; Department of Medicine, Hematology/Oncology Division., Xie P; Department of Medicine, Hematology/Oncology Division., Cowan M; Department of Obstetrics and Gynecology., Huang H; Department of Obstetrics and Gynecology., Cardenas H; Department of Obstetrics and Gynecology., Keathley R; Department of Obstetrics and Gynecology.; Driskill Graduate Training Program in Life Sciences, and., Tanner EJ; Department of Obstetrics and Gynecology.; Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA., Fleming GF; Department of Medicine, Hematology/Oncology Division, University of Chicago, Chicago, Illinois, USA., Moroney JW; Department of Medicine, Hematology/Oncology Division, University of Chicago, Chicago, Illinois, USA., Pant A; Northwestern Medicine, Lake Forest Hospital, Lake Forest, Illinois, USA., Akasha AM; Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA., Davuluri RV; Department of Biomedical Informatics, Stony Brook University, Stony Brook, New York, USA., Kocherginsky M; Department of Obstetrics and Gynecology.; Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.; Division of Biostatistics, Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA., Zhang B; Department of Medicine, Hematology/Oncology Division.; Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA., Matei D; Department of Obstetrics and Gynecology.; Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.; Jesse Brown VA Medical Center, Chicago, Illinois, USA.
المصدر: The Journal of clinical investigation [J Clin Invest] 2022 Jul 15; Vol. 132 (14).
نوع المنشور: Clinical Trial, Phase II; Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Print Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE
أسماء مطبوعة: Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
Original Publication: New Haven [etc.] American Society for Clinical Investigation.
مواضيع طبية MeSH: Neoplasm Recurrence, Local*/pathology , Ovarian Neoplasms*/drug therapy , Ovarian Neoplasms*/genetics , Ovarian Neoplasms*/pathology, Antineoplastic Combined Chemotherapy Protocols ; Epigenesis, Genetic ; Epigenomics ; Female ; Humans
مستخلص: BackgroundImmune checkpoint inhibitors (ICIs) have modest activity in ovarian cancer (OC). To augment their activity, we used priming with the hypomethylating agent guadecitabine in a phase II study.MethodsEligible patients had platinum-resistant OC, normal organ function, measurable disease, and received up to 5 prior regimens. The treatment included guadecitabine (30 mg/m2) on days 1-4, and pembrolizumab (200 mg i.v.) on day 5, every 21 days. The primary endpoint was the response rate. Tumor biopsies, plasma, and PBMCs were obtained at baseline and after treatment.ResultsAmong 35 evaluable patients, 3 patients had partial responses (8.6%), and 8 (22.9%) patients had stable disease, resulting in a clinical benefit rate of 31.4% (95% CI: 16.9%-49.3%). The median duration of clinical benefit was 6.8 months. Long-interspersed element 1 (LINE1) was hypomethylated in post-treatment PBMCs, and methylomic and transcriptomic analyses showed activation of antitumor immunity in post-treatment biopsies. High-dimensional immune profiling of PBMCs showed a higher frequency of naive and/or central memory CD4+ T cells and of classical monocytes in patients with a durable clinical benefit or response (CBR). A higher baseline density of CD8+ T cells and CD20+ B cells and the presence of tertiary lymphoid structures in tumors were associated with a durable CBR.ConclusionEpigenetic priming using a hypomethylating agent with an ICI was feasible and resulted in a durable clinical benefit associated with immune responses in selected patients with recurrent OC.Trial registrationClinicalTrials.gov NCT02901899.FundingUS Army Medical Research and Material Command/Congressionally Directed Medical Research Programs (USAMRMC/CDMRP) grant W81XWH-17-0141; the Diana Princess of Wales Endowed Professorship and LCCTRAC funds from the Robert H. Lurie Comprehensive Cancer Center; Walter S. and Lucienne Driskill Immunotherapy Research funds; Astex Pharmaceuticals; Merck & Co.; National Cancer Institute (NCI), NIH grants CCSG P30 CA060553, CCSG P30 CA060553, and CA060553.
التعليقات: Comment in: J Clin Invest. 2022 Jul 15;132(14):. (PMID: 35838045)
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معلومات مُعتمدة: R01 LM011297 United States LM NLM NIH HHS; R01 CA250101 United States CA NCI NIH HHS; R01 LM013722 United States LM NLM NIH HHS; R01 CA258857 United States CA NCI NIH HHS; P30 CA060553 United States CA NCI NIH HHS; R01 CA222963 United States CA NCI NIH HHS
فهرسة مساهمة: Keywords: Cancer; Cancer immunotherapy; Epigenetics; Immunology; Oncology
سلسلة جزيئية: ClinicalTrials.gov NCT02901899
تواريخ الأحداث: Date Created: 20220607 Date Completed: 20220718 Latest Revision: 20240301
رمز التحديث: 20240301
مُعرف محوري في PubMed: PMC9282926
DOI: 10.1172/JCI158800
PMID: 35671108
قاعدة البيانات: MEDLINE
الوصف
تدمد:1558-8238
DOI:10.1172/JCI158800