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How inhibiting both HDAC and PD-1 could improve immuno-oncology treatments



PD-1 inhibitors have revolutionized the treatment of several cancers, including melanoma and lung cancer, but some patients don't respond to them. HDAC inhibitors are approved to treat some blood cancers, but they had limited success so that HDAC and PD-1 inhibitors could be the answer to improving responses to both. Startup OnKure Therapeutics, which has an HDAC inhibitor in a phase 1 trial, and collaborators at the University of Colorado Cancer Center have early evidence in mice that the approach might work. -PD-1 therapy in mouse models of B-cell lymphoma, a University of Colorado team reported in the journal Cancer Immunology Research. They believe their observations of how the two drugs work together can improve the development of immuno-oncology combination treatments.

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RELATED: Syndax hits pause on entinostat / PD-1 program after midstage failures the combination's potency lies in a group of proteins called major histocompatibility complex (MHC). This protein helps the immune system to detect cancer cells by presenting antigens on the surface of the cells that label them as pathogens that should be eliminated. Problem is, about 60 percent or diffuse large B cell lymphomas downregulate MHC, "explained Jing Wang, MD, Ph.D., in a statement.

HDAC inhibitors, on the other hand, upregulate MHC. That causes cancer cells to make extra PD-L1, which interacts with PD-1. Therefore, administering OKI-179 in animals found it easier for PD-1 inhibitors to recognize the cancer and destroy it, Wang said

OnKure was founded in 2011 on an HDAC platform developed at the University of Colorado. The drug is similar to Celgene's HDAC inhibitor Istodax, but instead of having to be administered by infusion, it's delivered in pill form. , according to OnKure. [1 9659003] The University of Colorado group is not the first to suggest HDAC and PD-1 inhibition might be prominent in cancer. Last year, Syndax Pharmaceuticals announced that combining its HDAC inhibitor entinostat with Merck's anti-PD-1 drug, Keytruda produced partial responses in six patients with non-small cell lung cancer in a phase 1b / 2 trial. But in May this year, the company puts the combination trials on hold after suffering disappointing results from midphase studies combining entinostat with other checkpoint inhibitors. Australian scientists are testing a combination of the HDAC inhibitor Farydak, for example, with Incuron's investigational drug curaxin that targets a protein complex found only in tumor cells called FACT. Wang believes her team's mouse study goes a long way towards explaining why HDAC inhibitors have been largely ineffective. “If your HDAC inhibitor is up-regulating PD-L1, you're not going to do it work alone. But if you also block PD1, HDAC inhibition looks much more successful, "Wang says.


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