New drug screen uncovers small-molecule candidates for immuno-oncology

Cancer in newspaper clipping
A screen developed at Emory uses a mix of human immune cells and cancer cells to find new drug candidates for immuno-oncology. (PDPics/Pixabay)

Checkpoint inhibitors to treat cancer, such as Merck’s Keytruda and Bristol-Myers Squibb’s Opdivo, are antibodies: bulky proteins that have to be given intravenously. Those drugs are effective at removing barriers that normally prevent the immune system from recognizing and attacking cancer. But they’re inconvenient for patients, and not everyone responds well to them.

Scientists at Emory University wanted to search for small molecules—chemicals that can easily be packed into pills—that might have similar or even better immune-boosting effects. So they created a screening test that uses human immune cells to rapidly sort through vast libraries of chemicals and pinpoint the substances that can prompt the immune system to suppress cancer growth.

The system, dubbed HTiP, turned up an emerging class of drugs called IAP antagonists, which are already in studies to treat cancer. The screen confirmed that the drugs enhance the immune response to cancer, they reported in the journal Cell Chemical Biology. And they believe the test will be able to be expanded so it can uncover molecules that work in many different ways to activate an anticancer immune response.

INDUSTRY RESEARCH

Veeva 2019 Unified Clinical Operations Survey

Share your thoughts in this quick survey. The first 50 qualified respondents will receive a $5 Amazon gift card, and, in appreciation for your time, all qualified survey respondents will be entered in a drawing to win a $50 Amazon gift card.

HTiP, which stands for “High-Throughput Immunomodulator Phenotypic Screening Platform,” uses a mix of immune cells and cancer cells that carry a particular mutation in the KRAS gene. The mutation suppresses the immune system’s ability to fight the disease.

The Emory team screened 2,000 compounds using HTiP, searching for drug candidates that could reverse the effect of the KRAS mutation. They isolated the drug birinapant, an IAP antagonist that is currently being developed by Medivir, which is collaborating with Merck on a human trial of birinapant combined with Keytruda in patients with a variety of solid tumor types.

RELATED: Medivir delays pivotal HDAC trial as FDA discussions stall

The fact that HTiP pulled up IAP antagonists—and birinapant in particular—"was strong evidence for their relevance as immune enhancers,” said lead author Haian Fu, Ph.D., chair of the department of pharmacology and chemical biology at Emory University School of Medicine, in a statement. "It was a timely validation of our system."

Birinapant has encountered some bumps along the development path. It was originally developed by TetraLogic to treat hepatitis B, but safety concerns forced the company to halt an early trial and pull the plug on a planned initial public offering. Birinapant failed trials in myelodysplastic syndrome. Medavir bought the drug from TetraLogic in 2016.

Medivir and Merck are enrolling 135 cancer patients in their phase 1/2 combo trial, which they expect to complete in 2021.

Emory’s Fu says HTiP can use many types of immune cells to screen for immune-boosting compounds. And it can detect immune reactions that are either adaptive or innate. He adds that the system could be modified to test the effects of small-molecule drugs on other cancer-causing mutations.

The next step for Fu’s team is to expand HTiP so it can cover other mutations and screen many more compounds beyond the initial 2,000 they examined. “There are many targets inside the cell,” he said. “We want to shine a light on those intracellular targets.”