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Dexamethasone may curb efficacy of immune-checkpoint blockade in glioblastoma

Clinical Cancer Research
Reuters Health - 03/12/2020 - Dexamethasone given to combat cerebral edema in patients with glioblastoma may negatively affect immunotherapy, according to work in mice and clinical data.

"There are many biologic, endogenous factors contributing to immunosuppression and immune evasion in glioblastoma," said Dr. David A. Reardon of Harvard Medical School, in Boston.

"Our work highlights a critical exogenous and iatrogenic factor - the use of dexamethasone for the treatment of symptomatic cerebral edema - that represents an additional and significant potential hurdle for immunotherapy among patients afflicted with these devastating tumors," he told Reuters Health by email.

In a statement, Dr. Reardon noted that cerebral edema is a common, potentially life-threatening complication in glioblastoma patients. Corticosteroid treatment can help suppress the inflammation in the brain, he added.

Dr. Reardon and colleagues first studied the effects of dexamethasone administered with programmed cell death protein 1 (PD-1) blockade to syngeneic murine glioblastoma models.

Dexamethasone reduced survival in both immunocompetent and immunosuppressed animals in a dose-dependent manner, they report in Clinical Cancer Research. This was true of addition of dexamethasone to anti-PD-1 therapy alone or to anti-PD-1 therapy along with radiotherapy, a standard treatment for patients with glioblastoma.

In particular, say the researchers, "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."

The team then went on to examine data from 181 patients with glioblastoma treated with either anti-PD-1 or anti-PD-L1 therapy who were followed for a median of 22 months after diagnosis. Most had had recurrent disease and about 35% were receiving dexamethasone at baseline.

Use of dexamethasone at any dose was associated with reduced overall survival and was the strongest identified negative risk factor. Even after multivariable adjustment, compared with no dexamethasone, dosage of less than 2 mg was associated with a significantly higher risk of death (hazard ratio, 2.16). For a higher dosage, the corresponding hazard ratio was 1.97.

"Our results suggest that we should try to avoid dexamethasone among patients with glioblastoma who are treated with immunotherapy, and if corticosteroids are clinically required, we should use these drugs judiciously," Dr. Reardon said in the stratement. "Further, our results highlight that other strategies for the treatment of cerebral edema that do not have such a broad anti-inflammatory effect critically need to be investigated."

SOURCE: https://bit.ly/2VoVK03 Clinical Cancer Research, online November 25, 2020.

By David Douglas

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