Pancreatic cancer, which affects about 60,000 Americans per annum, is one of the deadliest sorts of cancer. After diagnosis, fewer than 10 percent of patients survive for five years.
While some chemotherapies are initially effective, pancreatic tumors often become immune to them. The disease has also proven difficult to treat with newer approaches like 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, which may be a combination of three drugs that help boost the body’s own immune defenses against tumors, is predicted to enter clinical trials later this year.
“We don’t have tons of excellent options for treating carcinoma. It’s a devastating disease clinically,” says William Freed-Pastor, a senior postdoc at MIT’s Koch Institute for Integrative Cancer Research. “If this approach led to durable responses in patients, it might make an enormous impact in a minimum of a subset of patients’ lives, but we’d like to ascertain how it’ll actually perform in trials.”
Freed-Pastor, who is additionally a medical oncologist at Dana-Farber Cancer Institute, is that the lead author of the new study, which appears today in the neoplastic cell. Tyler Jacks, the David H. Koch Professor of Biology and a member of the Koch Institute, is that the paper’s senior author.
The body’s system contains T cells which will recognize and destroy cells that express cancerous proteins, but most tumors create a highly immunosuppressive environment that disables these T cells, helping the tumor to survive.
Immune checkpoint therapy (the commonest sort of immunotherapy currently getting used clinically) works by removing the brakes on these T cells, rejuvenating them in order that they can destroy tumors. One class of immunotherapy drug that has shown success in treating many sorts of cancer targets the interactions between PD-L1, a cancer-linked protein that turns off T cells, and PD-1, the T cell protein that PD-L1 binds to. Drugs that block PD-L1 or PD-1, also called checkpoint inhibitors, are approved to treat cancers like melanoma and carcinoma, but they need little or no effect on pancreatic tumors.
Some researchers had hypothesized that this failure might be thanks to the likelihood that pancreatic tumors don’t express as many cancerous proteins, referred to as neoantigens. this is able to give T cells fewer targets to attack, in order that even when T cells were stimulated by checkpoint inhibitors, they wouldn’t be ready to identify and destroy tumor cells.
However, some recent studies had shown, and therefore the new MIT study confirmed, that a lot of pancreatic tumors neutralize fact express cancer-specific neoantigens. This finding led the researchers to suspect that perhaps a special sort of brake, aside from the PD-1/PD-L1 system, was disabling T cells in carcinoma patients.
In a study using mouse models of carcinoma, the researchers found that actually, PD-L1 isn’t highly expressed on carcinoma cells. Instead, most carcinoma cells express a protein called CD155, which activates a receptor on T cells referred to as TIGIT.
When TIGIT is activated, the T cells enter a state referred to as “T cell exhaustion,” during which they’re unable to mount an attack on pancreatic tumor cells. In an analysis of tumors far away from carcinoma patients, the researchers observed TIGIT expression and T cell exhaustion from about 60 percent of patients, and that they also found high levels of CD155 on tumor cells from patients.
“The CD155/TIGIT axis functions during a very similar thanks to the skilled PD-L1/PD-1 axis. TIGIT is expressed on T cells and is a brake to those T cells,” Freed-Pastor says. “When a TIGIT-positive T cell encounters any cell expressing high levels of CD155, it can essentially shut that T cell down.”
The researchers then began to ascertain if they might use this data to rejuvenate exhausted T cells and stimulate them to attack pancreatic tumor cells. They tested a spread of combinations of experimental drugs that inhibit PD-1 and TIGIT, alongside another sort of drug called a CD40 agonist antibody.
CD40 agonist antibodies, a number of which are currently being clinically evaluated to treat carcinoma, are drugs that activate T cells and drive them into tumors. In tests in mice, the MIT team found that drugs against PD-1 had little effect on their own, as has previously been shown for carcinoma. They also found that a CD40 agonist antibody combined with either a PD-1 inhibitor or a TIGIT inhibitor was ready to halt tumor growth in some animals, but didn’t substantially shrink tumors.
However, once 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 the animals given this treatment, and in 25 percent of the mice, the tumors disappeared completely. Furthermore, the tumors didn’t regrow after the treatment was stopped. “We were obviously quite excited that,” Freed-Pastor says.
Working with the Lustgarten Foundation for carcinoma Research, which helped to fund this study, the MIT team sought out two pharmaceutical companies who between them have a PD-1 inhibitor, TIGIT inhibitor, and CD40 agonist antibody in development. None of those drugs are FDA-approved yet, but they need each reached phase 2 clinical trials. A clinical test on the triple combination is predicted to start later this year.
“This work uses highly sophisticated, genetically engineered mouse models to research the small print of immune suppression in pancreas cancer, and therefore the results have pointed to potential new therapies for this devastating disease,” Jacks says. “We are pushing as quickly as possible to check these therapies in patients and are grateful for the Lustgarten Foundation and get up to Cancer for his or her help in supporting the research.”
Alongside the clinical test, the MIT team plans to research which sorts of pancreatic tumors might respond best to the present drug combination. they’re also doing further animal studies to ascertain if they will boost the treatment’s effectiveness beyond the 50 percent that they saw during this study.
In addition to the Lustgarten Foundation, the research was funded by get up To Cancer, the Hughes Medical Institute, Dana-Farber/Harvard Cancer Center, the Runyon Cancer Research Foundation, and therefore the National Institutes of Health.