Dexamethasone use could reduce immune checkpoint inhibitor viability in glioblastoma patients

Overview

• Post By : Kumar Jeetendra


• Source: American Association for Cancer Research


• Date: 25 Nov,2020

Bottom Line: One of patients with glioblastoma getting an immune checkpoint inhibitor, people who obtained the corticosteroid dexamethasone at baseline for cerebral edema had significantly worse overall survival.

Journal Where the Study was Released: Clinical Cancer Research, a journal of the American Association for Cancer Research

Author: David A. Reardon, MD, clinical director of the Center for Neuro-Oncology in Dana-Farber Cancer Institute in Boston

“Cerebral edema is a common yet potentially life-threatening complication for patients with glioblastoma, and treatment with corticosteroids can help to suppress the inflammation in the brain,” he added.

How the Study was Conducted & Outcomes: Reardon and colleagues assessed the effect of concurrent dexamethasone administration with a resistant checkpoint inhibitor (anti-PD-1 therapy) in syngeneic murine glioblastoma models.

Within an immunosensitive mouse model, which is responsive to immune checkpoint blockade, the researchers found that the addition of dexamethasone to anti-PD-1 therapy resulted in reduced survival in a dose-dependent method.

Additionally, in an immunoresistant mouse model, which Reardon noted is more representative of human glioblastoma, the addition of dexamethasone to anti-PD-1 therapy or anti-PD-1 therapy plus radiotherapy also led to reduced survival.

“Within our preclinical studies, we found that steroids had a significant detrimental effect on the efficacy of anti-PD-1 treatment, in an immunosensitive version, which over-predicts the benefit of immune checkpoint blockade in glioblastoma patients,” said Reardon.

The researchers analyzed overall survival data in 181 patients with glioblastoma treated with either anti-PD-1 or anti-PD-L1 therapy at Dana-Farber Cancer Institute who were diagnosed before April 1, 2019.

This patient population was heterogeneous, with patients receiving treatment through a clinical trial or on a compassionate use basis; roughly 76 percent were treated for recurrence, and roughly 24 percent were treated for a new analysis.

Historically, patients with glioblastoma have been empirically treated with dexamethasone, even without symptoms, with many clinicians prescribing steroids for prolonged periods of time, out of a concern that patients may start to develop edema. Our study was designed to look at that paradigm of clinical practice, particularly in the immunotherapy era, and determine if there could be negative consequences associated with dexamethasone use among patients with glioblastoma treated with immune checkpoint inhibitors.”

David A. Reardon, MD, Clinical Director, Center for Neuro-Oncology, Dana-Farber Cancer Institute

Reardon and colleagues evaluated the potential detrimental effect of dexamethasone with multivariable analysis, where they corrected for many different factors, including disease setting (newly diagnosed with recurrent), tumor volume at therapy initiation, age, and extent of resection, one of the 163 patients who had complete annotated data for relevant prognostic factors.

Compared with patients who were not taking dexamethasone at baseline, patients treated with dexamethasone had approximately twice the risk of death.

Further, baseline usage of dexamethasone was the most powerful identified negative risk factor for overall survival.

Author’s comments:”Our results imply that we should try and prevent dexamethasone among patients with glioblastoma that are treated with immunotherapy, and when corticosteroids are clinically required, we should use these drugs judiciously,” Reardon said.

“Further, our results highlight that other strategies for the treatment of cerebral edema which don’t have such a broad anti-inflammatory effect seriously need to be investigated.”

Study limitations: Limitations of the study include the retrospective nature of the clinical investigations. Further, in their preclinical studies, the researchers solely evaluated the effect of dexamethasone on the efficacy of anti-PD-1 treatment.

“Whether the very same observations would happen with other immunomodulatory checkpoint targeting agents, or other immunotherapy treatments–such as vaccines, adoptive cellular therapies, or genetically engineered oncolytic viruses–remains to be assessed,” Reardon said.

This study was also funded by the National Institutes of Health.