Picking the Winners: Study Sheds Light on Possible Best Targets for Pancreatic Cancer Vaccine

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Memorial Sloan Kettering physician-scientist Vinod Balachandran, who specializes in treating pancreatic cancer

Physician-scientist Vinod Balachandran says the new findings could guide researchers as they design therapeutic vaccines to fight pancreatic cancer.

Pancreatic cancer is known for its grim prognosis. But remarkably, a very small group of patients manage to beat the odds and survive. In the past few years, researchers at Memorial Sloan Kettering Cancer Center (MSK), led by physician-scientist Vinod Balachandran, have made groundbreaking discoveries about why a lucky few seem to avoid having their cancer return after surgery.

The key appears to be proteins in the pancreatic tumors, called neoantigens, which alert the immune system to keep the cancer at bay. This finding led to a promising clinical trial to treat people with pancreatic cancer by stimulating their immune system with neoantigen-based vaccines.

Now new research provides even more insights into the relationship between the immune system and pancreatic cancer. It further bolsters the idea that a therapeutic vaccine based on carefully selected neoantigens could be effective in people with the disease.

“Our finding provides more evidence that the immune system recognizes neoantigens in pancreatic cancer, and that we are on the right track in picking these neoantigens,” Dr. Balachandran says. “This could be useful for personalized vaccines for pancreatic cancer — which urgently needs better treatments — and other cancers as well.”

The study, led by Dr. Balachandran and computational biologist Benjamin Greenbaum, along with computer scientist Marta Luksza at the Icahn School of Medicine at Mount Sinai, is published May 19, 2022, in Nature.

Learning From Long-Term Pancreatic Cancer Survivors

The latest finding builds on an important discovery made by Dr. Balachandran’s team in 2017. They reported in the journal Nature that long-term pancreatic cancer survivors have tumors that are especially immunogenic, meaning their tumors are spontaneously recognized and attacked by immune cells called T cells. In these patients, neoantigen-specific T cells were found patrolling the body even a decade or more after treatment. The researchers concluded that the T cells may have been keeping the cancer from returning.

Significantly, the team also found neoantigens in the tumors of people who were not long-term survivors. Although these neoantigens were not seen spontaneously by T cells, their presence suggested that vaccines incorporating the right neoantigens might spur the immune cells into action — bringing the same anti-cancer effect.

This further supports the idea that activating the immune system, perhaps with mRNA vaccines, might be effective.
Vinod P. Balachandran physician-scientist

Based on this finding, Dr. Balachandran and MSK colleagues launched a clinical trial in 2019 to test a vaccine using messenger RNA (mRNA) in people with pancreatic cancer. (It’s the same technology used for the COVID-19 vaccine). In this case, each pancreatic cancer vaccine is personalized for the individual patient and contains neoantigens most likely to stimulate T cells.

This clinical trial, the first to use mRNA to treat pancreatic cancer, was completed a year ahead of schedule in 2021, despite challenges posed by the pandemic. The results of the trial are currently being analyzed.

While the trial progressed, the researchers wanted to learn more about neoantigens in pancreatic cancer. Could they develop a better strategy to choose the neoantigens seen by the immune system? Could this strategy be key to developing an effective vaccine?

In the new Nature study, Drs. Balachandran and Greenbaum and colleagues offer further evidence that neoantigens are important targets for T cells. They made this discovery by studying how pancreatic tumors in long-term survivors evolved over 10 years and changed their genetic makeup to adapt to the immune response.

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How the Immune System Prunes Cancer Cells

At the heart of this finding is a theory called cancer immunoediting. In 1957, Frank MacFarlane Burnet and Lewis Thomas proposed that the immune system was constantly snuffing out most — although clearly not all — potential cancers by destroying cells with troublesome antigens. Immunologists concluded that as cancer develops, the immune system prunes away the most immunogenic or vulnerable cancer cells. In most people — those who don’t live long — the remaining tumor is less noticeable and susceptible to the immune system, and the cancer can grow unimpeded.

Cancer immunoediting had been demonstrated in mice but not shown conclusively in humans. To determine whether the human immune system naturally edits cancers, the research team studied pairs of pancreatic cancer samples up to a decade apart taken from 15 patients. The first sample was from the primary tumor removed by surgery. The second was from the cancer that had returned, usually in a different spot.

“Previously, we’ve only had data from one time point,” Dr. Greenbaum says. “Here, we could compare predictions about clonal evolution and what features might be more or less likely to be recognized by the immune system with the actual evolution of the tumor over a long period.”

The team picked neoantigens that were recognized by T cells in the first sample and tested if these neoantigens had been already pruned away in the second sample as the cancer started to recur. The team was able to identify neoantigens removed by T cells in samples up to a decade apart.

The strategy to pick these neoantigens could be important for a pancreatic cancer vaccine. Even though the neoantigens don’t drive the cancer themselves, they attract immune attention that snuffs out any recurrence. The research suggested that if T cells do recognize neoantigens, it could possibly cause pancreatic cancer to remain dormant for years.

“This is more evidence that the immune system is important in pancreatic cancer,” Dr. Balachandran says. “It further supports the idea that activating the immune system, perhaps with mRNA vaccines, might be effective.”

The finding was possible only because the researchers were able to study enough patients who lived a long time. The researchers say this type of discovery was made possible by MSK’s unique resources — both the specific group of long-term pancreatic cancer survivors and the infrastructure and expertise supporting genomic analysis.

“The way that computational biologists and physician-scientists communicate and collaborate is especially strong here,” Dr. Greenbaum says. “I don’t think this research would be possible at other places if you look at all the pieces that came together for this finding.”

 

Key Takeaways
  • A small number of people with pancreatic cancer manage to survive.
  • This appears to be due to proteins in their tumors called neoantigens that the immune system targets.
  • New research confirms that the immune system recognizes neoantigens up to 10 years later.
  • This suggests therapeutic vaccines can be effective against pancreatic cancer.
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This work was supported by NIH U01 CA224175, a Stand Up To Cancer Convergence Award, a Damon Runyon Clinical Investigator Award, the Avner Pancreatic Cancer Foundation, the NCI Cancer Center Support Grant (P30 CA08748), Cycle for Survival®, and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology.

Dr. Balachandran is co-inventor on a patent application related to work on antigen cross-reactivity. Drs. Balachandran and Greenbaum are co-inventors on a patent application related to work on neoantigen quality modeling. Dr. Balachandran has received research support from Bristol Myers Squibb and Genentech.