New immunotherapy strategy can eliminate pancreatic tumors in mice

Pancreatic cancer, which affects approximately 60,000 Americans each year, is one of the deadliest forms of cancer. After diagnosis, less than 10 percent of patients survive for five years.

While some chemotherapy drugs are initially effective, pancreatic tumors often become resistant to them. The disease has also proven difficult to treat with new approaches such as immunotherapy. However, a team of researchers from MIT has now developed an immunotherapy strategy and has shown that it can eliminate pancreatic tumors in mice.

The new therapy, which is a combination of three drugs that help strengthen the body’s own immune defenses against tumors, is expected to enter clinical trials later this year.

We don’t have a lot of good options for treating pancreatic cancer. It is a clinically devastating disease. If this approach led to lasting responses in patients, it would have a big impact on at least a subset of patients’ lives, but we have to see how it actually works in trials. “

William Freed-Pastor, Senior Postdoctoral Fellow, MIT Koch Institute for Integrative Cancer Research

Freed-Pastor, who is also a medical oncologist at the Dana-Farber Cancer Institute, is the lead author of the new study, which appears today in Cancer cell. Tyler Jacks, David H. Koch professor of biology and fellow of the Koch Institute, is the lead author of the article.

Immune attack

The body’s immune system contains T cells that are able to recognize and destroy cells expressing cancer proteins, but most tumors create a highly immunosuppressive environment that turns off these T cells, helping the tumor to survive.

Immune checkpoint therapy (the most common form of immunotherapy currently used clinically) works by removing the brakes on these T cells, rejuvenating them so they can destroy tumors. A class of immunotherapy drugs that has been successful in treating many types of cancer targets interactions between PD-L1, a cancer-related protein that deactivates T cells, and PD-1, the T cell protein to which PD- L1 binds. Drugs that block PD-L1 or PD-1, also called checkpoint inhibitors, have been approved to treat cancers such as melanoma and lung cancer, but have very little effect on pancreatic tumors.

Some researchers had speculated that this failure could be due to the possibility that pancreatic tumors do not express as many cancerous proteins, called neoantigens. This would give T cells fewer targets to attack, so that even when T cells were stimulated by checkpoint inhibitors, they wouldn’t be able to identify and destroy tumor cells.

However, some recent studies have shown, and the new MIT study has confirmed, that many pancreatic tumors actually express cancer-specific neoantigens. This discovery led researchers to suspect that a possibly different type of frenulum, other than the PD-1 / PD-L1 system, was deactivating T cells in patients with pancreatic cancer.

In a study using mouse models of pancreatic cancer, researchers found that in fact, PD-L1 is not highly expressed on pancreatic cancer cells. Instead, most pancreatic cancer cells express a protein called CD155, which activates a receptor on T cells known as TIGIT.

When TIGIT is activated, T cells enter a state known as “T cell depletion”, in which they are unable to launch an attack on pancreatic tumor cells. In an analysis of tumors taken from pancreatic cancer patients, researchers observed TIGIT expression and T cell depletion in about 60% of patients, and they also found elevated CD155 levels. on tumor cells of patients.

“The CD155 / TIGIT axis functions very similarly to the more established PD-L1 / PD-1 axis. TIGIT is expressed on T cells and acts as a brake on those T cells,” explains Freed-Pastor. “When a TIGIT-positive T cell encounters a cell expressing high levels of CD155, it can essentially shut down that T cell.”

Combination of drugs

The researchers then set out to see if they could use this knowledge to rejuvenate depleted T cells and stimulate them to attack pancreatic tumor cells. They tested a variety of experimental drug combinations that inhibit PD-1 and TIGIT, as well as another type of drug called the CD40 agonist antibody.

CD40 agonist antibodies, some of which are currently under clinical evaluation to treat pancreatic cancer, are drugs that activate T cells and cause them to form tumors. In tests on mice, the MIT team found that the PD-1 drugs had little effect on their own, as has already been shown for pancreatic cancer. They also found that a CD40 agonist antibody combined with a PD-1 inhibitor or TIGIT inhibitor was able to stop tumor growth in some animals, but did not significantly shrink tumors.

However, when they combined CD40 agonist antibodies with both a PD-1 inhibitor and a TIGIT inhibitor, they found a dramatic effect. Pancreatic tumors shrank in about half of the animals that received this treatment and in 25 percent of the mice the tumors disappeared completely. In addition, the tumors did not grow back after stopping treatment. “We were obviously very excited about it,” said Freed-Pastor.

In collaboration with the Lustgarten Foundation for Pancreatic Cancer Research, which helped fund this study, the MIT team looked for two pharmaceutical companies that have between them a PD-1 inhibitor, a TIGIT inhibitor, and a developing CD40 agonist antibody. None of these drugs are FDA approved yet, but they have each reached Phase 2 clinical trials. A triple combination clinical trial is expected to begin later this year.

“This work uses very sophisticated genetically engineered mouse models to study the details of immune suppression in pancreatic cancer, and the results indicated potential new therapies for this devastating disease,” Jacks said. “We are working as quickly as possible to test these therapies in patients and are grateful to the Lustgarten Foundation and Stand Up to Cancer for their help in supporting the research. “

Along with the clinical trial, the MIT team plans to analyze what types of pancreatic tumors might respond best to this combination of drugs. They’re also doing other animal studies to see if they can increase the effectiveness of the treatment beyond the 50 percent they saw in this study.

In addition to the Lustgarten Foundation, the research was funded by Stand Up To Cancer, the Howard Hughes Medical Institute, the Dana-Farber / Harvard Cancer Center, the Damon Runyon Cancer Research Foundation, and the National Institutes of Health.