Combining cancer therapies for better patient outcomes

A Triple-combo of drugs targeting pancreatic cancer is going into 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 initial experiments the new research demonstrated pancreatic tumors shrink when a novel combination treatment is administered.

A combination of many anti-cancer drugs, and combining different therapeutic approaches may infact lead to the best results. Hopfully this upcoming trial will shed light on if this is a good way forward.