Epigenetic Drugs May Be Key to Improving Cancer Patients’ Response to Immunotherapies

Epigenetic Drugs May Be Key to Improving Cancer Patients’ Response to Immunotherapies

In the past decade, immunotherapy treatment approaches designed to fight cancer using the body’s natural defenses have attracted tremendous attention. This led to advances in the synthesis and development of new agents, some of which have now reached the clinic.

Several successful immunotherapy studies were presented at this summer’s American Society of Clinical Oncology (ASCO) conference in Chicago.

Ovarian cancer, which affects around 220,000 women per year, is the seventh-most common form of cancer worldwide. It is commonly treated with chemotherapy, but recent advances show that immunotherapy could be a better alternative.

“Cancer patients who respond to immunotherapy tend to have a prolonged response,” Rebecca C. Arend, MD, an assistant professor at the University of Alabama at Birmingham (UAB) Division of Gynecologic Oncology, said in a news release.

“It’s really exciting, because this is something that we don’t usually see with chemotherapy and 75 percent of patients recur within two years of receiving initial chemotherapy and surgery for ovarian cancer,” she said.

Lately, researchers have been focusing particularly on immune checkpoint inhibitors, such as PD-1 and CTLA-4 inhibitors. “Your body has a natural response of putting the brakes on the immune system,” said Arend, also an associate scientist in the Experimental Therapeutics Program at the UAB Comprehensive Cancer Center. “These drugs take those brakes off.”

Currently, checkpoint inhibitors like Opdivo (nivolumab), Yervoy (ipilimumab), and Keytruda (pembrolizumab) are approved for a number of indications. The PD-1 inhibitor Opdivo, for example, is now approved for subsets of patients with melanoma, non-small cell lung cancer, renal cell carcinoma, and Hodgkin’s lymphoma, and was just recently approved for head and neck squamous cell carcinoma.

But not all patients respond positively to these drugs. Researchers believe that one key factor distinguishing responders from nonresponders could be the amount of mutations seen in each patient’s tumor. “Mutation burden enhances the response to immunotherapy, probably because the tumor looks even more like non-self,” Arend said. “So more and more research is being done to look at ways that we can prime tumors to look like the ones in these good responders.”

Several human trial studies have shown that using checkpoint inhibitors in combination with epigenetic drugs may improve patients’ response to immunotherapy. There are several theories that might explain why this happens.

“One theory is that epigenetic drugs enhance immune modulator pathways,” Arend said. “Another is that you are causing more genomic disarray in the tumor itself. And there are papers that have shown that resistance to immunotherapy is because of epigenetic modification. So there could be multiple interactions.”

Other factors that may influence the response to this combination of drugs could be the timing, dosage, and sequence in how these drugs are administrated.

“Most of the human trials that are ongoing basically give the drugs at the same time,” Arend said. “I don’t know that that’s the way to go. It may be that you need to give the epigenetic drug first, followed by immunotherapy. And it may be more beneficial to give it upfront, rather than later on in the course of disease.”

To gain a better understanding of these factors, Arend is currently investigating the combination of immunotherapy and epigenetic drugs in laboratory models of ovarian cancer. In her studies, two types of epigenetic drugs — DNA methyltransferase inhibitors and histone deacetylase inhibitors — will be tested in combination with a PD-1 inhibitor.

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