Preclinical Study Finds HDAC Inhibitor’s Effect Tied to Immunity Status
Posted: Tuesday, December 4, 2018
Using a mouse model of ovarian cancer, University of Alabama at Birmingham researchers examined if, why, and how the histone deacetylase (HDAC) inhibitor entinostat would work to enhance tumor shrinkage and prolong survival. In immunocompetent mice, entinostat accomplished these goals, reported Haller J. Smith, MD, and colleagues in the journal Cancer.
The Alabama investigators demonstrated that entinostat treatment altered expression of “genes involved in antigen presentation, T-cell inhibition and exhaustion, and T-cell effector function…[which] correlated with an increase in tumor-infiltrating, cluster of differentiation 8–positive T cells,” they wrote. These results, however, seemed to be contingent on adaptive immunity. Thus, Dr. Smith and colleagues suggested that entinostat’s efficacy in the model was “not caused entirely by direct cytotoxic or cytostatic effects of the drug but…predominantly through an indirect mechanism that involves stimulation of adaptive immunity.”
The agent may lead to augmented adaptive effector functions and perhaps reduced T-cell exhaustion in ovarian cancer, the investigators proposed. “The most salient application of entinostat and other epigenetic modifiers may be in combination with other immune-potentiating modalities, like checkpoint inhibitors, to stimulate more durable antitumor immunity in women with ovarian cancer,” they wrote. This could be why, when used as single agents or in combination with chemotherapy, HDAC inhibitors such as entinostat have not shown significant efficacy in phase I and II clinical trials in patients with ovarian cancer.