Triple-combo of drugs targeting pancreatic cancer looks to human trials
Impressive new preclinical work from a team at MIT has found a combination of three experimental immunotherapy drugs could help shrink, or even eliminate, pancreatic tumors. Each of the three drugs have demonstrated safety in early-stage human trials and the researchers hope to begin a trial testing the novel triple combo by the end of the year.
“We don’t have a lot of good options for treating pancreatic cancer,” explains lead author William Freed-Pastor. “It’s a devastating disease clinically.”
Cancer cells cleverly evade the body’s immune defenses by expressing proteins that shut down immune T cells. Many modern cancer immunotherapy treatments are designed to inhibit this mechanism, allowing the body’s immune cells a better chance to seek out and destroy tumor cells.
These therapies, known as checkpoint inhibitors, are currently used to treat some cancers, including lung cancer and melanoma. However, pancreatic cancers have been notoriously resistant to current checkpoint inhibitor therapies and only now are scientists understanding why.
One common checkpoint inhibitor treatment in current use works by blocking the interaction between a cancer protein called PD-L1 and a receptor on immune T-cells called PD-1. The new research confirms a long-held hypothesis finding PD-L1 is not highly expressed on pancreatic cancer cells, explaining why modern checkpoint inhibitor therapies are largely ineffective.
But the new research also discovered a similar mechanism is at play in pancreatic cancers. Here, the cancer evades immune defenses by expressing a protein called CD155. This protein engages a receptor on T cells known as TIGIT, which stifles the immune attack on cancer cells.
“The CD155/TIGIT axis functions in a very similar way to the more established PD-L1/PD-1 axis,” explains Freed-Pastor. “TIGIT is expressed on T cells and serves as a brake to those T cells. When a TIGIT-positive T cell encounters any cell expressing high levels of CD155, it can essentially shut that T cell down.”
Across several mouse experiments the new research demonstrated pancreatic tumors shrink when a novel combination treatment is administered. The treatment combined a PD-1 checkpoint inhibitor with a TIGIT inhibitor and then added a third drug known as a CD40 antibody agonist to the mix.
CD40 antibody agonists are new drugs designed to help supercharge immune T cells. They have been found to amplify the effect of checkpoint inhibitor therapies and the new study reveals combining them with both PD-1 and TIGIT inhibitors led to pancreatic tumor reductions in 50 percent of mouse tests. Pancreatic tumors were seen to disappear completely in about a quarter of the animal experiments.
“This work uses highly sophisticated, genetically engineered mouse models to investigate the details of immune suppression in pancreas cancer, and the results have pointed to potential new therapies for this devastating disease,” notes Tyler Jacks, senior author on the new study.
Because all three experimental drugs are already in advanced human trial stages the researchers say there is potential for rapid clinical translation. The plan is to begin testing this triple combination of immunotherapy drugs in human pancreatic cancer patients by the end of the year.
“If this approach led to durable responses in patients, it would make a big impact in at least a subset of patients’ lives, but we need to see how it will actually perform in trials,” says Freed-Pastor.
The new study was published in the journal Cancer Cell.