دورية أكاديمية
Concurrent Dexamethasone Limits the Clinical Benefit of Immune Checkpoint Blockade in Glioblastoma.
| العنوان: | Concurrent Dexamethasone Limits the Clinical Benefit of Immune Checkpoint Blockade in Glioblastoma. |
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| المؤلفون: | Iorgulescu JB; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts., Gokhale PC; Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Speranza MC; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Eschle BK; Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Poitras MJ; Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Wilkens MK; Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Soroko KM; Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Chhoeu C; Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Knott A; Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Gao Y; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Lim-Fat MJ; Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Baker GJ; Department of Systems Biology, Harvard Medical School, Boston, Massachusetts., Bonal DM; Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts., Nguyen QD; Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts., Grant GRL; University of Glasgow Medical School, Glasgow, Scotland, United Kingdom., Ligon KL; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Broad Institute of Harvard and MIT, Cambridge, Massachusetts., Sorger PK; Department of Systems Biology, Harvard Medical School, Boston, Massachusetts., Chiocca EA; Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts., Anderson AC; Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts.; Department of Immunology, Blavatnik Institute, Harvard Medical School and Evergrande Center for Immunologic Diseases, Harvard Medical School, Boston, Massachusetts., Kirschmeier PT; Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Sharpe AH; Department of Immunology, Blavatnik Institute, Harvard Medical School and Evergrande Center for Immunologic Diseases, Harvard Medical School, Boston, Massachusetts., Freeman GJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Reardon DA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. david_reardon@dfci.harvard.edu.; Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. |
| المصدر: | Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2021 Jan 01; Vol. 27 (1), pp. 276-287. Date of Electronic Publication: 2020 Nov 25. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: The Association Country of Publication: United States NLM ID: 9502500 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-3265 (Electronic) Linking ISSN: 10780432 NLM ISO Abbreviation: Clin Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Denville, NJ : The Association, c1995- |
| مواضيع طبية MeSH: | Brain Edema/*drug therapy , Brain Neoplasms/*therapy , Dexamethasone/*pharmacology , Glioblastoma/*therapy , Immune Checkpoint Inhibitors/*pharmacology, Animals ; B7-H1 Antigen/antagonists & inhibitors ; Brain Edema/etiology ; Brain Neoplasms/complications ; Brain Neoplasms/genetics ; Brain Neoplasms/mortality ; Cell Line, Tumor/transplantation ; Chemoradiotherapy/methods ; Dexamethasone/therapeutic use ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Interactions ; Female ; Follow-Up Studies ; Glioblastoma/complications ; Glioblastoma/genetics ; Glioblastoma/mortality ; Humans ; Immune Checkpoint Inhibitors/therapeutic use ; Isocitrate Dehydrogenase/genetics ; Kaplan-Meier Estimate ; Mice ; Prognosis ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Retrospective Studies ; Tumor Microenvironment/drug effects ; Tumor Microenvironment/immunology |
| مستخلص: | Purpose: Dexamethasone, a uniquely potent corticosteroid, is frequently administered to patients with brain tumors to decrease tumor-associated edema, but limited data exist describing how dexamethasone affects the immune system systemically and intratumorally in patients with glioblastoma (GBM), particularly in the context of immunotherapy. Experimental Design: We evaluated the dose-dependent effects of dexamethasone when administered with programmed cell death 1 (PD-1) blockade and/or radiotherapy in immunocompetent C57BL/6 mice with syngeneic GL261 and CT-2A GBM tumors. Clinically, the effect of dexamethasone on survival was evaluated in 181 patients with isocitrate dehydrogenase (IDH) wild-type GBM treated with PD-(L)1 blockade, with adjustment for relevant prognostic factors. Results: Despite the inherent responsiveness of GL261 to immune checkpoint blockade, concurrent dexamethasone administration with anti-PD-1 therapy reduced survival in a dose-dependent manner. Concurrent dexamethasone also abrogated survival following anti-PD-1 therapy with or without radiotherapy in immune-resistant CT-2A models. Dexamethasone decreased T-lymphocyte numbers by increasing apoptosis, in addition to decreasing lymphocyte functional capacity. Myeloid and natural killer cell populations were also generally reduced by dexamethasone. Thus, dexamethasone appears to negatively affect both adaptive and innate immune responses. As a clinical correlate, a retrospective analysis of 181 consecutive patients with IDH wild-type GBM treated with PD-(L)1 blockade revealed poorer survival among those on baseline dexamethasone. Upon multivariable adjustment with relevant prognostic factors, baseline dexamethasone administration was the strongest predictor of poor survival [reference, no dexamethasone; <2 mg HR, 2.16; 95% confidence interval (CI), 1.30-3.68; P = 0.003 and ≥2 mg HR, 1.97; 95% CI, 1.23-3.16; P = 0.005]. Conclusions: Our preclinical and clinical data indicate that concurrent dexamethasone therapy may be detrimental to immunotherapeutic approaches for patients with GBM. (©2020 American Association for Cancer Research.) |
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| معلومات مُعتمدة: | U54 CA225088 United States CA NCI NIH HHS; R01 NS110942 United States NS NINDS NIH HHS; P50 CA101942 United States CA NCI NIH HHS; K12 CA090354 United States CA NCI NIH HHS; R01 CA229400 United States CA NCI NIH HHS; P01 AI039671 United States AI NIAID NIH HHS; R01 CA203873 United States CA NCI NIH HHS; P01 CA163205 United States CA NCI NIH HHS; P50 CA165962 United States CA NCI NIH HHS; P01 CA069246 United States CA NCI NIH HHS; P01 CA236749 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (B7-H1 Antigen) 0 (CD274 protein, human) 0 (Immune Checkpoint Inhibitors) 0 (Pdcd1 protein, mouse) 0 (Programmed Cell Death 1 Receptor) 7S5I7G3JQL (Dexamethasone) EC 1.1.1.41 (Isocitrate Dehydrogenase) |
| تواريخ الأحداث: | Date Created: 20201126 Date Completed: 20220110 Latest Revision: 20221005 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC8034990 |
| DOI: | 10.1158/1078-0432.CCR-20-2291 |
| PMID: | 33239433 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1557-3265 |
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| DOI: | 10.1158/1078-0432.CCR-20-2291 |