HDAC inhibition may combat resistance to anti-PD-1 therapy in patients with melanoma

Source: EurekAlert!, March 2019

ATLANTA — A combination of the experimental histone deacetylase (HDAC) inhibitor entinostat with the anti-PD-1 therapeutic pembrolizumab (Keytruda) showed clinical responses in patients with melanoma that had progressed on prior anti-PD-1 treatment, according to results from the ENCORE 601 phase Ib/II clinical trial presented at the AACR Annual Meeting 2019, March 29-April 3.

“While a large group of patients have derived benefit from treatment with checkpoint inhibitors, many still develop resistance to these therapies," said Ryan Sullivan, MD, assistant professor of hematology and oncology at Massachusetts General Hospital Cancer Center. “A number of studies, including this trial, are endeavoring to identify key immunotherapy combinations to overcome resistance to checkpoint blockade immunotherapy."

HDAC inhibitors can modulate the immune system by suppressing regulatory cells, such as myeloid-derived suppressor cells and regulatory T cells, and by increasing antigen expression on cancerous cells, two mechanisms that may counteract resistance to checkpoint inhibition, explained Sullivan. “Adding HDAC inhibition to anti-PD-1 treatment against tumors that have developed resistance to checkpoint blockade immunotherapy may lead to re-recognition of the tumor by the immune system and down-modulation of immune-suppressive elements in the tumor microenvironment, thereby increasing the efficacy of anti-PD-1 therapy," he added.