An experimental drug may be effective against a deadly form of pancreatic cancer when used in combination with other immune-boosting therapies, according to a study cover online Nov. 12 in Cancer Cell
The findings revolve around the immune system, which attacks foreign organisms like bacteria while leaving the body's own cells alone. To spare normal cells, the system uses "checkpoint" sensors to turn off immune cells when they receive the right signal. The body recognizes tumors as abnormal, but cancer cells inappropriately flip the checkpoint "off switch" to avert the immune attack.
The current results in mice and lab-grown human tumor cells showed that the study drug, called GSK547, helps another drug class called checkpoint inhibitors to mount a more aggressive attack against tumor cells seeking to evade notice. The GSK547 combo doubled survival to 50 days in mice with pancreatic ductal adenocarcinoma while similar mice given only checkpoint inhibitors lived 25 days.
Receptor-interacting serine / threonine-protein kinase 1?
??????The study was performed by scientists at the NYU School of Medicine and its Perlmutter Cancer Center in collaboration with scientists at GlaxoSmithKline, the manufacturer of the drug being developed. Moreover, the company expects to launch a Phase I clinical trial in November using a new drug meant for safety testing in humans and named GSK095.
"Our results support the potential effectiveness of blocking to signaling pathway in pancreatic ductal adenocarcinoma in a way that potently complements existing treatments," says George Miller, MD, the HL Pachter Professor at NYU Langone Health and Perlmutter.
"If clinical trials prove successful, this could be really promising for many people with an end-stage disease," says Miller, who also serves as vice chair for research in the Department of Surgery at NYU Langone.end-stage disease," says Miller, who also serves as vice chair for research in the Department of Surgery at NYU Langone.
Miller, the co-senior study investigator, and hepatobiliary surgeon, says GSK547 and GSK095 work by blocking the action of an enzyme called receptor-interacting serine / threonine-protein kinase 1, or RIP1. This enzyme regulates immune cells called macrophages that home in on tumors, but then "decides" to become a cell type that suppresses the immune response based on signals given off by cancer cells.
Miller adds that such macrophages in pancreatic ductal adenocarcinoma cannot turn on "killer" T cells, which would normally attack cancer cells. Specifically, the new study found in laboratory tests of human pancreatic cancer cells that treatment with the RIP1-inhibiting GSK547 brought about a doubling of killer T cell activation and a fivefold decrease in the macrophage-influenced T cell type that suppresses the immune system.
Pancreatic ductal adenocarcinoma is the most common form of pancreatic cancer, which strikes over 50,000 Americans annually and nearly the same number, says Miller. Current treatment options, he says, are few and focus on pain relief, or surgery and radiation therapy to prolong life.
Previous attempts at harnessing the immune system to increase killer T cell counts have failed, probably Miller said because there were too few of the cells needed to attack cancer, with tumors continuing to grow and spread. Miller says his team has not seen this problem with GSK547, which operates "upstream" in the immune system, before T cell activation, and as a "master regulator."
Drugs used in combination with GSK547 were a PD1 inhibitor, a checkpoint-blocking therapy that prevents cancer cells from evading the immune system, and an ICOS activator that helps prime the immune system's T cells to identify cancer cells and target them for an attack.
"Our approach is designed to turn 'cold' tumors that evade the immune system into 'hot' tumors, which the system can target," says study co-first author Wei Wang, MD, a postdoctoral fellow in the Department of Surgery at NYU Langone and Perlmutter. "Ultimately, we hope that our future research will reveal that RIP1 kinase inhibition can be applied to several cancers that are resistant to checkpoint inhibition."
The next Phase I clinical trial on the drug will use GSK095, which is taken as a twice-a-day pill for as long as it is tolerated with no disease progression. The study will measure the side effects of the drug candidate along with its ability to treat cancer. The RIP1-kinase inhibiting drug will be tested alone, and, in a separate set of patients, in combination with pembrolizumab, at checkpoint inhibitor.