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’ve had limited success so far.
Could combining HDAC and PD-1 inhibitors 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.
Adding OnKure’s drug, OKI-179, overcame resistance to anti-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 worked together could improve the development of immuno-oncology combination treatments.
The researchers discovered that the key to the combination’s potency lies in a group of proteins called major histocompatibility complex (MHC). This protein family helps the immune system’s T cells recognize 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 of diffuse large B cell lymphomas downregulate MHC," explained Jing Wang, M.D., 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 the animals seemed to make it easier for PD-1 inhibitors to recognize the cancer and destroy it, Wang said.
OnKure was founded in 2011 based on an HDAC platform developed at the University of Colorado. The company raised $7 million in a series A financing in May 2018, which allowed it to advance OKI-179 to phase 1 trials. 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.
The University of Colorado group is not the first to suggest combining HDAC and PD-1 inhibition might be promising 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 of this year, the company put the combination trials on hold after suffering disappointing results from midphase studies combining entinostat with other checkpoint inhibitors.
Meanwhile, several academic researchers are investigating various possibilities for improving responses to HDAC inhibition. 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. The combination looked promising in mouse models of neuroblastoma, the researchers said late last year.
Wang believes her team’s mouse study goes a long way toward explaining why HDAC inhibitors have been largely ineffective. “If your HDAC inhibitor is upregulating PD-L1, you're not going to make it work alone. But if you also block PD1, HDAC inhibition looks much more successful," Wang says.