Birinapant and Checkpoint Inhibitors in Cancer immunotherapy

If scientists want to improve the ability of immune cells to kill cancer cells, then many other tools are needed to discover a larger library of more traditional “small molecules”. What they need, first and foremost, is a way to classify them, a platform for screening thousands of drugs.

This is reported by Emory researchers in a new paper on cell chemistry biology. They also demonstrated that a class of drugs called IAP antagonists, one of which has been applied in clinical trials, can promote immune activity against cancer cells in their systems.

Although checkpoint inhibitorsare now approved by the FDA for the treatment of many types of cancer, many patients did not benefit from it. Finding drugs that relax other parts of the immune response can improve outcomes, especially for those cancer types where checkpoint inhibitors are not effective.

The lead author, Dr. Haian Fu, director of the Department of Pharmacology and Chemical Biology at Emory University School of Medicine, said that drug discovery in cancer immunotherapy focuses on extracellular regulatory molecules that are easily accessible.

“This is a powerful co-culture system that enables high-throughput screening of cancer immunotherapy,” Fu said. “There are many targets in the cell. We want to illuminate these intracellular targets.”

In collaboration with Fu, Xiulei Mo, PhD, an Instructor, and his colleagues created a system to test whether compounds can enhance the ability of human immune cells to inhibit cancer cell growth. They call it HTiP for “high-throughput immunomodulatory phenotypic screening platforms.”

The HTiP system uses a mixture of human immune cells in combination with cancer cells carrying known growth-driven mutations. Emory’s researchers began with the well-known oncogene KRAS and compared the effects of cancer cells (colon and lung cancer cell lines) with and without KRAS mutations. The presence of KRAS mutations is immunosuppressive, which means that in the Emory system, KRAS mutations provide resistance against immune cells to kill cancer cells.

Mo screened a library of approximately 2,000 known compounds to isolate the drug birinapant, which was proved to be able to enhance the activity of immune cells on cancer cells and which had little effect on cancer cells. Birinapant is part of a class of drugs called IAP antagonists that have begun to be studied by scientists on their anticancer activity.

“This is a strong evidence of their importance as immune enhancers,” Fu said. “This is a timely verification of our system.” In fact, birinapant is being tested in conjunction with checkpoint inhibitors. The researchers found that the other two IAP antagonists have similar effects in the same system.

The screening platform is independent of the mechanism of KRAS immunosuppression or the precise type of immune cells. Fu noted that most checkpoint inhibitors appear to act on cytotoxic T cells, but the screening platform uses a combination of immune cell types. “The effects in our system may come from any or all of these cell types,” he said.

All that is required is the effect of the compound to reverse the KRAS mutation. He said the system can be easily modified to test the effects of other oncogenic mutations, or to focus on a specific type of tumor antigen-specific immune cells. The team also plans to expand its screening work because 2,000 compounds are actually small compared to the number of potential drugs.