Novel Combination Therapy Can Potentially Eliminate Pancreatic Tumors in Mice

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08/09/2021

Photo: William Freed-Pastor

genengnews.com

The American Cancer Society estimates about 60,430 people will be diagnosed with pancreatic cancer in the United States in 2021. It is one of the deadliest forms of cancer; after diagnosis, fewer than 10% of patients survive for five years.

Pancreatic tumors often become resistant to chemotherapies and have proven difficult to treat with newer approaches. However, a new immunotherapy developed by MIT researchers may provide hope as it has been shown to eliminate pancreatic tumors in mice.

The findings are published in the journal Cancer Cell in a paper titled, “The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer.”

“The CD155/TIGIT axis can be co-opted during immune evasion in chronic viral infections and cancer. Pancreatic adenocarcinoma (PDAC) is a highly lethal malignancy, and immune-based strategies to combat this disease have been largely unsuccessful to date,” wrote the researchers.

“We corroborate prior reports that a substantial portion of PDAC harbors predicted high-affinity MHC class I-restricted neoepitopes and extend these findings to advanced/metastatic disease. Using multiple preclinical models of neoantigen-expressing PDAC, we demonstrate that intratumoral neoantigen-specific CD8+ T cells adopt multiple states of dysfunction, resembling those in tumor-infiltrating lymphocytes of PDAC patients.”

The researchers used a combination of three drugs that help boost the body’s own immune defenses against tumors, and it is expected to enter clinical trials later this year.

“We don’t have a lot of good options for treating pancreatic cancer. It’s a devastating disease clinically,” said William Freed-Pastor, PhD, a senior postdoc at MIT’s Koch Institute for Integrative Cancer Research. “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.”

The new MIT study confirmed, that many pancreatic tumors do express cancer-specific neoantigens. This finding led the researchers to suspect that perhaps a different type of brake, other than the PD-1/PD-L1 system, was disabling T cells in pancreatic cancer patients.

In a study using mouse models of pancreatic cancer, the 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, the T cells enter a state known as “T-cell exhaustion,” in which they are unable to mount an attack on pancreatic tumor cells. In an analysis of tumors removed from pancreatic cancer patients, the researchers observed TIGIT expression and T-cell exhaustion from about 60% of patients, and they also found high levels of CD155 on tumor cells from patients.

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

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

In tests in mice, they found that drugs against PD-1 had little effect on their own, as has previously been shown for pancreatic cancer. They also discovered that a CD40 agonist antibody combined with either a PD-1 inhibitor or a TIGIT inhibitor was able to halt tumor growth in some animals, but did not substantially shrink tumors.

However, when they combined CD40 agonist antibodies with both a PD-1 inhibitor and a TIGIT inhibitor, they observed that pancreatic tumors shrank in about half of the animals given this treatment. “We were obviously quite excited about that,” Freed-Pastor said.

Working with the Lustgarten Foundation for Pancreatic Cancer Research, which helped to fund the 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. The drugs have reached Phase II clinical trials, and a clinical trial on the triple combination is expected to begin later this year.

“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,” explained Tyler Jacks, PhD, the David H. Koch professor of biology and a member of the Koch Institute, and is the paper’s senior author. “We are pushing as quickly as possible to test these therapies in patients and are grateful for the Lustgarten Foundation and Stand Up to Cancer for their help in supporting the research.”

The MIT researchers plan to analyze which types of pancreatic tumors might respond best to this drug combination. Further studies are needed to boost the treatment’s effectiveness beyond the 50% seen.

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