INFORMATION - DENDRITIC CELL THERAPY

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Researchers find that three immunotherapy drugs given together can eliminate pancreatic tumors in mice. 

Anne Trafton | MIT News Office - MIT Massachusetts Institute of Technologie

Link:  https://news.mit.edu/2021/pancreatic-cancer-immunotherapy-cd155-0805

Pancreatic cancer, which affects approximately 60,000 Americans each year, is one of the deadliest cancers. After diagnosis, fewer than 10 percent of patients survive five years. While some chemotherapies are initially effective, pancreatic tumors often become resistant to them. The disease has proven difficult to treat even with newer approaches such as immunotherapy. However, a team of MIT researchers has now developed an immunotherapy strategy and shown that it can eliminate pancreatic tumors in mice. 

The new therapy, a combination of three drugs that help strengthen the body's immune defense against tumors, is expected to enter clinical trials this year. 

“We don’t have many good options for treating pancreatic cancer. It’s a devastating disease clinically,” says William Freed-Pastor, a senior postdoctoral fellow at MIT’s Koch Institute for Integrative Cancer Research. “If this approach led to durable responses in patients, it would have a big impact in at least part of the patient's life, but we need to see how it actually performs in trials.” 

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, the David H. Koch Professor of Biology and a member of the Koch Institute, is the senior author of the paper. 

Immune attack 

The body's immune system contains T cells that can recognize and destroy cells that express cancerous proteins, but most tumors create a highly immunosuppressive environment that deactivates these T cells and helps the tumor survive. 

Immune checkpoint therapy (the most common form of immunotherapy currently used clinically) works by removing the brakes on these T cells and rejuvenating them so they can destroy tumors. A class of immunotherapy drugs that has shown success in treating many types of cancer targets the interactions between PD-L1, a cancer-linked protein that shuts down 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 they have very little effect on pancreatic tumors. 

Some researchers had hypothesized that this failure could be due to the possibility that pancreatic tumors do not express as many cancer proteins called neoantigens. This would provide T cells with fewer targets, so even if T cells were stimulated by checkpoint inhibitors, they would be unable to identify and destroy tumor cells. However, some recent studies had shown, and the new MIT study confirmed, that many pancreatic tumors do indeed express cancer-specific neoantigens. This finding led researchers to believe that perhaps a type of brake other than the PD-1/PD-L1 system deactivated T cells in pancreatic cancer patients. 

In a study using mouse models of pancreatic cancer, researchers found that PD-L1 is actually 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 exhaustion,” in which they are unable to attack pancreatic tumor cells. In an analysis of tumors removed from pancreatic cancer patients, researchers observed TIGIT expression and T-cell exhaustion in about 60 percent of patients, and they also found high levels of CD155 on patients' tumor cells. 

“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 these T cells,” says Freed-Pastor. “When a TIGIT-positive T cell encounters a cell that expresses high levels of CD155, it can essentially shut down that T cell.” 

The researchers then set out to see whether they could use this knowledge to rejuvenate exhausted T cells and stimulate them to attack pancreatic tumor cells. 

They tested a variety of combinations of experimental drugs that inhibit PD-1 and TIGIT, along with another type of drug called CD40 agonist antibodies. 

CD40 agonist antibodies, some of which are currently being clinically studied to treat pancreatic cancer, are drugs that activate T cells and drive them into tumors. In tests on mice, the MIT team found that PD-1 drugs alone had little effect, as previously shown for pancreatic cancer. They also found that a CD40 agonist antibody combined with either a PD-1 inhibitor or a TIGIT inhibitor could stop tumor growth in some animals, but did not shrink tumors significantly. 

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. Additionally, the tumors did not grow back after treatment was stopped. “We were of course very happy about that,” says Freed-Pastor. 

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

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

In addition to the clinical trial, the MIT team plans to analyze which types of pancreatic tumors might respond best to this drug combination. They are also conducting further animal studies to see if they can increase the treatment's effectiveness 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.