In this new study involving a mouse model of ovarian cancer, researchers evaluated the effects of entinostat on adaptive immune responses.
A study conducted in mice found that the histone deacetylase (HDAC) inhibitor entinostat can enhance immune responses in ovarian cancer. In the future, trials combining entinostat with immune checkpoint blockade or other immunomodulatory agents may improve antitumor response rates in patients with ovarian cancer.
“The introduction of targeted therapies has done little to impact overall survival for women with ovarian cancer, and responses to immunotherapy have been disappointing, with overall response rates ≤ 15% with currently available checkpoint inhibitors,” wrote study authors led by Rebecca C. Arend, MD, of the University of Alabama at Birmingham.
Previous research has shown that entinostat leads to increased expression of major histocompatibility complex II (MHCII) on ovarian cancer cells, which corresponds with higher numbers of tumor-infiltrating lymphocytes, as well as improved survival. In the group’s new study involving a mouse model of ovarian cancer, they evaluated the effects of entinostat on adaptive immune responses. The results were published in Cancer.
First, they tested entinostat in an immunocompetent mouse, and found that the agent led to a significant reduction in tumor growth compared with a control (P = .046 at day 11 of treatment). A second experiment showed that entinostat led to an improvement in median overall survival, at 74 days compared with 62 days in control mice (P = .005), for a hazard ratio of 0.26 (95% CI, 0.06–1.21).
Next, the researchers tested whether the expression of 46 genes known to be related to adaptive immunity changed upon treatment. They found that entinostat resulted in significant changes to microRNA expression in 21 of the 46 genes. Notably, the immune checkpoint molecule PD-L1 was also upregulated with entinostat treatment. This, along with several other changes to gene expression, “suggest that entinostat alters the tumor microenvironment by upregulating antigen-presenting machinery, as well as PD-L1, while also contributing a more robust T-cell response,” the authors wrote.
They also showed that entinostat increases the expression of MHCII on the surface of ovarian tumor cells, and flow cytometry showed that it also increases the frequency of CD8+ T cells in the tumor (21.0% vs 18.0% in control; P = .04). In contrast, CD4+ and regulatory T-cell populations remained largely unchanged. A repetition of experiments in a mouse model that was immunocompromised showed that an intact immune response is necessary for the entinostat effects to be seen.
“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,” the authors concluded.
In an accompanying editorial, Ira Surolia, MD, and Susan E. Bates, MD, of Columbia University Medical Center in New York, wrote that the findings are interesting both because they demonstrate the single-agent activity of entinostat in ovarian cancer and because that activity involves effects on the immune system. “This sets the stage for early-phase clinical trials with entinostat alone in ovarian cancer and also in combination with immunotherapies,” they wrote. “Entinostat makes an appealing candidate for this type of combination therapy, given its long half-life and predicted, sustained gene expression.”