Iorgulescu et al. evaluated the impact of dexamethasone on response to anti-PD-1 therapy in glioblastoma (GBM) in immune-sensitive GL261 and immune-resistant CT-2A GBM intracranial murine models. Concurrent dexamethasone administration decreased the survival benefit of anti-PD-1 therapy, with or without radiotherapy, in a dose-dependent manner. Dexamethasone increased apoptosis, decreased activation of CD4+ and CD8+ T cells, and decreased intratumoral and systemic CD4+ T cell, CD8+ T cell, and NK cell populations in vivo. In patients with IDH wild-type GBM undergoing anti–PD-(L)1 therapy, dexamethasone use was associated with poor survival.
Contributed by Shishir Pant
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 ³2 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.
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. (2) Experimen
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. (2) Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts. (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. (4) Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts. (5) Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts. (6) Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts. (7) Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts. (8) Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts. (9) Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts. (10) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. (11) Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. (12) Department of Systems Biology, Harvard Medical School, Boston, Massachusetts. (13) Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts. (14) Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts. (15) University of Glasgow Medical School, Glasgow, Scotland, United Kingdom. (16) 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. (17) Department of Systems Biology, Harvard Medical School, Boston, Massachusetts. (18) Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts. (19) 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. (20) Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts. (21) Department of Immunology, Blavatnik Institute, Harvard Medical School and Evergrande Center for Immunologic Diseases, Harvard Medical School, Boston, Massachusetts. (22) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. (23) 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.
