GlaxoSmithKline’s experimental drug GSK095 is designed to work in tandem with checkpoint inhibiting medicines in the hopes of empowering the immune system to launch a more aggressive attack against tumors than it does with checkpoint inhibitors alone. Early results from a preclinical trial of a related GSK drug suggest that the combo holds promise in treating pancreatic cancer—so much so that the company is launching a phase 1 study of the drug in combination with Merck’s blockbuster PD1 checkpoint inhibitor Keytruda.
In a study performed by scientists from GSK and New York University, GSK095 combined with a checkpoint inhibitor prolonged survival in mouse models of pancreatic ductal adenocarcinoma to 50 days, while mice given the checkpoint inhibitor alone lived just 25 days, according to a statement.
GSK095 works by blocking the enzyme receptor-interacting serine/threonine-protein kinase 1 (RIP1), which is a key regulator of immune cells known as macrophages. These cells travel to tumors, but then they transform into cells that suppress the immune response rather than enhance it. Macrophages cannot activate the killer T cells that would normally attack cancer cells.
In lab experiments with human pancreatic cancer cells, the NYU and GSK team discovered that the RIP1 inhibitor doubled the activation of killer T cells and tamped down the production of immune-suppressing cells by fivefold. In mice, they combined the RIP1 inhibitor with a PD1 blocker and an “ICOS activator,” a drug that helps T cells spot and target cancer cells, according to the study, which was published in the journal Cancer Cell.
“Our approach is designed to turn ‘cold’ tumors that evade the immune system into ‘hot’ tumors, which the system can target,” said co-author Wei Wang, M.D., a postdoctoral fellow in the Department of Surgery at NYU School of Medicine and its Perlmutter Cancer Center, in the statement.
Pancreatic ductal adenocarcinoma affects 50,000 people in the U.S. each year and is almost always fatal. It’s the most common form of pancreatic cancer.
The potential for RIP1 inhibitors to boost checkpoint inhibition in cancer will no doubt be of interest to oncology researchers, who have been actively searching for ways to extend the usefulness of drugs like Keytruda. Checkpoint inhibitors fail in many patients, and even when they work, resistance can occur. Last year, scientists from Roche’s Genentech uncovered data from a trial of the company’s checkpoint inhibitor Tecentriq showing that the protein TGF-beta was present in high amounts in patients who did not respond to the drug. They went on to show that in mice, they could improve the Tecentriq efficacy by giving TGF-beta inhibitor along with the drug.
RIP1 kinase inhibitors have already generated some excitement in biotech, particularly in central nervous system and inflammatory disease research. Earlier this month, Sanofi laid out $125 million for two RIP1 inhibitors being developed by Denali, including DNL747, which is in a phase 1 study in amyotrophic lateral sclerosis. In that case, Denali’s scientists believe that inhibiting RIP1 stops the production of inflammatory molecules in the body.
In GSK's phase 1 trial, GSK095 will be given to pancreatic cancer patients as an oral drug twice a day. The company is recruiting 220 patients for the trial, which will be conducted in four stages over a period of two years. The drug will be tested as both a monotherapy and in combination with Keytruda, the company said in a listing on ClinicalTrials.gov.
The NYU researchers believe their insights into RIP1 could be applied to other cancers, as well. They say it offers advantages over other methods that have been tried to boost populations of killer T cells, because GSK’s RIP1 inhibitor operates before T cells are activated and then acts as a “master regulator” that continues to enhance the immune response, they said.