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The Clinical Application of Tumor Treating Fields Therapy in Glioblastoma
Published on: April 16, 2019
Concurrent Dexamethasone Limits the Clinical Benefit of Immune Checkpoint Blockade in Glioblastoma
J Bryan Iorgulescu1,2, Prafulla C Gokhale3, Maria C Speranza1
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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.
Insights
Dexamethasone use with immunotherapy for glioblastoma (GBM) may reduce survival. This corticosteroid negatively impacts immune cells and responses, showing poorer outcomes in patients receiving it alongside PD-(L)1 blockade.
Area of Science:
- Neuro-oncology
- Immunology
- Pharmacology
Background:
- Dexamethasone is used to reduce brain tumor edema in glioblastoma (GBM).
- Its systemic and intratumoral immune effects, especially with immunotherapy, are not well understood.
- Glioblastoma treatment often involves radiation and immunotherapy.
Purpose of the Study:
- To investigate the dose-dependent effects of dexamethasone on immune responses in GBM models.
- To evaluate the impact of dexamethasone on survival in mice and patients with GBM undergoing immunotherapy.
- To determine if dexamethasone interferes with programmed cell death 1 (PD-1) blockade efficacy.
Main Methods:
- Preclinical study using immunocompetent mice with syngeneic GL261 and CT-2A GBM tumors treated with dexamethasone, anti-PD-1 therapy, and/or radiotherapy.
- Clinical analysis of 181 patients with IDH wild-type GBM receiving PD-(L)1 blockade, assessing survival based on baseline dexamethasone use.
- Dose-dependent evaluation of dexamethasone's impact on T-lymphocytes, myeloid cells, and natural killer cells.
Main Results:
- Dexamethasone reduced survival in mice with GBM, particularly when given with anti-PD-1 therapy, in a dose-dependent manner.
- Concurrent dexamethasone abrogated survival benefits of anti-PD-1 therapy in both responsive and resistant GBM models.
- Dexamethasone decreased T-lymphocyte numbers via apoptosis and reduced their function, also impacting myeloid and NK cells.
- Clinical data showed poorer survival in GBM patients on baseline dexamethasone treated with PD-(L)1 blockade; it was the strongest predictor of poor survival.
Conclusions:
- Concurrent dexamethasone administration appears detrimental to immunotherapeutic approaches for glioblastoma.
- Dexamethasone negatively affects both adaptive and innate immune responses, compromising immunotherapy efficacy.
- Findings suggest a need to reconsider dexamethasone use in GBM patients undergoing immunotherapy.
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