mRNA vaccine could stop pancreatic cancer

The key to these vaccines appears to be proteins in pancreatic tumors called neoantigens, which alert the immune system to keep cancer at bay. (CREDIT: Creative Commons)

Messenger RNA (mRNA) vaccines may be the hottest topic in science right now as they have helped turn the tide in the fight against COVID-19. But even before the pandemic hit, Memorial Sloan Kettering Cancer Center researchers were already working on using mRNA vaccine technology to treat cancer.

Vinod Balachandran, a medical scientist at the David M. Rubenstein Center for Pancreatic Cancer Research and a member of the Human Oncology and Pathogenesis Program and the Parker Institute for Cancer Immunotherapy, is leading the only clinical trial testing mRNA vaccines against pancreatic cancer. The key to these vaccines appears to be proteins in pancreatic tumors called neoantigens, which alert the immune system to keep cancer at bay.

Vaccines are made individually for each person. The hope is that the vaccine will stimulate the production of certain immune cells called T cells that recognize pancreatic cancer cells. This may reduce the risk of cancer coming back after surgical removal of the underlying tumor.

In 8 of the 16 patients studied, the vaccines activated T cells that recognize the patient’s own pancreatic cancer. These patients also experienced delayed recurrence of pancreatic cancer, suggesting that vaccine-activated T cells may have the desired effect to keep pancreatic cancer under control.

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Dr. Balachandran discusses how collaboration with BioNTech, which developed the Pfizer-BioNTech COVID-19 vaccine, led to a potential treatment for pancreatic cancer.

What inspired the use of the pancreatic cancer vaccine?

There was a lot of interest in using immunotherapy to treat pancreatic cancer because nothing else worked very well. We thought that immunotherapy was promising because of the research we started about seven years ago. A small group of patients with pancreatic cancer manage to overcome difficulties and survive after tumor removal. We looked at tumors taken from these selected patients and saw that the tumors were especially rich in immune cells, especially T cells. Something in the tumor cells seemed to be sending out a signal that alerted the T cells and attracted them.

Later, we discovered that these signals were proteins called neoantigens, which T cells recognize as foreign, causing the immune system to attack. Tumor cells accumulate these neoantigens as a result of genetic mutations during division. In most people with pancreatic cancer, these neoantigens are not detected by immune cells, so the immune system does not perceive the tumor cells as a threat. But in our study, we saw that the neoantigens in pancreatic cancer survivors were different—they didn’t go unnoticed. Basically, they opened tumors to T cells by getting T cells to recognize them.

Even more strikingly, we found that T cells recognizing these neoantigens circulated in the blood of these rare patients for up to 12 years after surgical removal of pancreatic tumors. This robust immune response was similar to autovaccination. T cells had a memory of neoantigens as a threat, similar to how vaccines induce memory and protect against pathogens for up to decades. This discovery led us to believe that artificially inducing this effect in other patients with pancreatic cancer might be effective.

How might an mRNA vaccine work against pancreatic cancer?

My colleagues and I published our findings on immune protection in long-lived patients after pancreatic cancer in the journal Nature in November 2017. While working on this, we were also looking for ways to deliver neoantigens to patients in the form of vaccines. We were particularly interested in mRNA vaccines, a new technology that we considered very promising. Vaccines use mRNA, part of the genetic code, to teach your body’s cells to make a protein that will trigger an immune response.

Coincidentally, at this time, BioNTech co-founder and CEO Ugur Sahin emailed us that he had read our article and was interested in our ideas. At the end of 2017, we flew to Mainz, Germany, where BioNTech is based. Then it was still a little-known company. We had lunch with Ugur and his team in Mainz, as well as Ira Mellman of Genentech, who has been working with BioNTech to bring mRNA vaccine technology to cancer patients. We discussed the potential of mRNA vaccines for pancreatic cancer.

Creating an effective cancer vaccine is difficult. Since cancer originates from our own cells, it is much more difficult for the immune system to distinguish proteins in cancer cells from foreign ones compared to proteins in pathogens such as viruses. But important advances in cancer biology and genome sequencing are now enabling the development of vaccines that can tell the difference. This builds on important work done at MSK that has shown how important tumor mutations are in triggering an immune response. We were all optimistic about the potential and decided to move forward.

How it works? How is an mRNA vaccine adapted to an individual human tumor?

After surgical removal of the patient’s pancreatic tumor, genetic sequencing of the tumor is performed to look for mutations that produce the best neoantigenic proteins, that is, the neoantigens that appear most foreign to the immune system. The vaccine is made with mRNA specific for these proteins in that person’s tumor. During the manufacture of the vaccine, the patient receives a single dose of a checkpoint inhibitor drug. We believe that checkpoint inhibitors may work in combination with these vaccines to enhance the immune response to tumors.

When an mRNA vaccine is injected into a person’s bloodstream, it causes immune cells called dendritic cells to produce neoantigenic proteins. Dendritic cells also train the rest of the immune system, including T cells, to recognize and attack tumor cells that express the same proteins. Because T cells are on high alert to kill cells carrying these proteins, the cancer may be less likely to return.

In December 2019, we included the first patient in a clinical trial to see if this vaccine is safe. The process of making vaccines was complex. For example, COVID-19 vaccines are not personalized — each vaccine is the same — so they are easy to produce in large batches.

The mRNA cancer vaccine must be made individually for each patient, depending on their tumor. To do this, we have to perform a very complex operation to remove a tumor, send a sample to Germany, sequence it, make a vaccine, and then send it back to New York – all in a short time. Fortunately, we were up to the task and completed the recruitment of 20 patients almost a year ahead of schedule.

How did you manage to conduct a clinical trial in the midst of a pandemic?

When the pandemic hit, we knew we needed to adapt quickly so our patients didn’t get hurt. Thanks to our research team, led by Cristina Olchese, we have coordinated a very complex logistics to ensure that the trial runs smoothly. When we started, our estimated time to complete the trial was two and a half years. We finished it in 18 months.

This was due to the excellent leadership of the Department of Surgery, Jeffrey Drebin, and the Chief of the Hepatopancreatobiliary Service, William Jarnagin. Dr. Drebin recognized the importance of this study from the very beginning and was the strongest supporter of the study, including the majority of patients. Medical oncologist Eileen O’Reilly, medical scientist Jedd Volchok, biologist Taha Mergub, and computational biologist Ben Greenbaum also provided invaluable assistance with this trial. We also received tremendous research support from the Stand Up 2 Cancer/Lustgarten foundation, without whom this research would not have been possible.

What do these recent discoveries tell us about the use of mRNA vaccines to treat pancreatic cancer?

This shows that we are on the right track. The mRNA vaccine can induce the production of T cells that recognize pancreatic cancer cells. It’s very exciting to see that a personalized vaccine could use the immune system to fight pancreatic cancer, which urgently needs more effective treatments, as well as other cancers.

What are the next steps for testing an mRNA vaccine?

We will continue to analyze the trial data to better understand what factors help the vaccine work in patients. We hope to use this information to improve vaccines so that they are more effective and work for more people with pancreatic cancer. In an effort to improve the vaccine, we published a new study in May 2022. Nature who suggested ways to select the best neoantigens.

Our team here at MSK is fantastic, as are the BioNTech and Genentech teams that funded the study. We will move forward with a larger study to test personalized mRNA vaccines in more patients with pancreatic cancer.

Vinod Balachandran says mRNA vaccines can stimulate the immune system to recognize and attack pancreatic cancer cells. (CREDIT: Memorial Sloan Kettering Cancer Center)

It was a great example of MSK’s visionary vision in the field of cancer treatment to bring the most exciting medicines to cancer patients. We worked with mRNA vaccines before they became popular to test our scientific findings in patients.

Key Findings

• Some people with pancreatic cancer survive many years after diagnosis.

• In these patients, the immune system prevents the cancer from returning.

• A messenger RNA vaccine based on this concept is being tested in combination with another type of immunotherapy.

• Initial results show that the vaccine has the desired effect on the immune system.

To learn more about science and technology, visit our New Discoveries section at The bright side of the news.

Note: Materials courtesy of Memorial Sloan-Kettering Cancer Center above. Content can be edited for style and length.

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