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Translational Cancer Mechanisms and Therapy

Concurrent Dexamethasone Limits the Clinical Benefit of Immune Checkpoint Blockade in Glioblastoma

J. Bryan Iorgulescu, Prafulla C. Gokhale, Maria C. Speranza, Benjamin K. Eschle, Michael J. Poitras, Margaret K. Wilkens, Kara M. Soroko, Chhayheng Chhoeu, Aine Knott, Yan Gao, Mary Jane Lim-Fat, Gregory J. Baker, Dennis M. Bonal, Quang-Dé Nguyen, Gareth R. L. Grant, Keith L. Ligon, Peter K. Sorger, E. Antonio Chiocca, Ana C. Anderson, Paul T. Kirschmeier, Arlene H. Sharpe, Gordon J. Freeman and David A. Reardon
J. Bryan Iorgulescu
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
2Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
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  • ORCID record for J. Bryan Iorgulescu
Prafulla C. Gokhale
3Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Maria C. Speranza
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Benjamin K. Eschle
3Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Michael J. Poitras
3Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Margaret K. Wilkens
3Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Kara M. Soroko
3Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Chhayheng Chhoeu
3Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Aine Knott
3Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Yan Gao
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Mary Jane Lim-Fat
4Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Gregory J. Baker
5Department of Systems Biology, Harvard Medical School, Boston, Massachusetts.
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Dennis M. Bonal
6Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Quang-Dé Nguyen
6Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Gareth R. L. Grant
7University of Glasgow Medical School, Glasgow, Scotland, United Kingdom.
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Keith L. Ligon
2Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
8Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
9Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
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Peter K. Sorger
5Department of Systems Biology, Harvard Medical School, Boston, Massachusetts.
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E. Antonio Chiocca
10Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts
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Ana C. Anderson
11Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts.
12Department of Immunology, Blavatnik Institute, Harvard Medical School and Evergrande Center for Immunologic Diseases, Harvard Medical School, Boston, Massachusetts.
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Paul T. Kirschmeier
3Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Arlene H. Sharpe
12Department of Immunology, Blavatnik Institute, Harvard Medical School and Evergrande Center for Immunologic Diseases, Harvard Medical School, Boston, Massachusetts.
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Gordon J. Freeman
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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David A. Reardon
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
4Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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  • For correspondence: david_reardon@dfci.harvard.edu
DOI: 10.1158/1078-0432.CCR-20-2291 Published January 2021
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Abstract

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.

This article is featured in Highlights of This Issue, p. 1

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Clin Cancer Res 2021;27:276–87

  • Received June 18, 2020.
  • Revision received August 24, 2020.
  • Accepted October 8, 2020.
  • Published first November 25, 2020.
  • ©2020 American Association for Cancer Research.
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Clinical Cancer Research: 27 (1)
January 2021
Volume 27, Issue 1
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Concurrent Dexamethasone Limits the Clinical Benefit of Immune Checkpoint Blockade in Glioblastoma
J. Bryan Iorgulescu, Prafulla C. Gokhale, Maria C. Speranza, Benjamin K. Eschle, Michael J. Poitras, Margaret K. Wilkens, Kara M. Soroko, Chhayheng Chhoeu, Aine Knott, Yan Gao, Mary Jane Lim-Fat, Gregory J. Baker, Dennis M. Bonal, Quang-Dé Nguyen, Gareth R. L. Grant, Keith L. Ligon, Peter K. Sorger, E. Antonio Chiocca, Ana C. Anderson, Paul T. Kirschmeier, Arlene H. Sharpe, Gordon J. Freeman and David A. Reardon
Clin Cancer Res January 1 2021 (27) (1) 276-287; DOI: 10.1158/1078-0432.CCR-20-2291

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Concurrent Dexamethasone Limits the Clinical Benefit of Immune Checkpoint Blockade in Glioblastoma
J. Bryan Iorgulescu, Prafulla C. Gokhale, Maria C. Speranza, Benjamin K. Eschle, Michael J. Poitras, Margaret K. Wilkens, Kara M. Soroko, Chhayheng Chhoeu, Aine Knott, Yan Gao, Mary Jane Lim-Fat, Gregory J. Baker, Dennis M. Bonal, Quang-Dé Nguyen, Gareth R. L. Grant, Keith L. Ligon, Peter K. Sorger, E. Antonio Chiocca, Ana C. Anderson, Paul T. Kirschmeier, Arlene H. Sharpe, Gordon J. Freeman and David A. Reardon
Clin Cancer Res January 1 2021 (27) (1) 276-287; DOI: 10.1158/1078-0432.CCR-20-2291
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