[Sept. 18, 2023: Vinod P. Balachandran, Memorial Sloan Kettering Cancer Center]

The key to these vaccines appears to be a protein in pancreatic tumors, called neoantigens, that alerts the immune system to ward off cancer. (Credit: Creative Commons)

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

Vinod Balachandran, a physician-scientist affiliated with 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, leads the only clinical trial testing mRNA vaccines for pancreatic cancer are doing. The key to these vaccines appears to be a protein in pancreatic tumors, called neoantigens, that alerts the immune system to ward off cancer.

Vaccines are made specifically 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 returning after the main tumor is removed by surgery.

In 8 of 16 patients studied, the vaccines activated T cells that recognize the patient’s own pancreatic cancer. A delay in pancreatic cancer recurrence was observed in these patients, suggesting that T cells activated by the vaccines may have the desired effect in keeping pancreatic cancer under control.

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

What was the motivation for using the vaccine against pancreatic cancer?

There has been a lot of interest in using immunotherapy for pancreatic cancer because nothing else has worked very well. We thought immunotherapy was promising because of the research that started about seven years ago. A small group of patients with pancreatic cancer manage to beat the odds and survive after the tumor is removed. We looked at tumors taken from these selected patients and saw that the tumors contained particularly large numbers of immune cells, particularly T cells. Something in the tumor cells was sending a signal that alerted the T cells and drew them in.

We later found that these signals were proteins called neoantigens that T cells recognize as foreign, causing the immune system to attack. Tumor cells accumulate these nascent antigens as a result of genetic mutations when they divide. 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 observed that neoantigens were different in pancreatic cancer survivors – they did not escape attention. In fact, they isolated the tumors from the T cells, causing the T cells to recognize them.

Even more surprising, we found that T cells that recognize these neoantigen antigens continued to circulate in the blood of these rare patients for 12 years after the pancreatic tumors were surgically removed. This persistent immune response was like an autovaccination. Neoantigens had memory in T cells as a threat, just as vaccines trigger memory and protect against pathogens for decades. This finding led us to think that artificially inducing this effect in other patients with pancreatic cancer might be effective.

How might mRNA vaccines work against pancreatic cancer?

My colleagues and I published our findings about immune protection in long-term pancreatic cancer survivors in 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 thought was quite promising. Vaccines use mRNA, a piece of genetic code, to teach cells in your body to make a protein that will trigger an immune response.

Coincidentally, at this time, Ugur Sahin, co-founder and CEO of BioNTech, emailed us that he had read our paper and was interested in our ideas. In late 2017, we flew to Mainz, Germany, where BioNTech is based. They were a little-known company even at that time. We had dinner with Ugur and his team in Mainz, as well as Genentech’s Ira Melman, who is working with BioNTech to bring mRNA vaccine technology to cancer patients. We discussed the potential of mRNA vaccines for pancreatic cancer.

Designing an effective cancer vaccine is difficult. Since cancer originates from our own cells, it is much more difficult for the immune system to recognize proteins in cancer cells as foreign than proteins from pathogens such as viruses. But significant advances in cancer biology and genomic sequencing have now made it possible to design vaccines that can tell the difference. This builds on important work done at MSK that has shown how important tumor mutations are for triggering the immune response. We were all optimistic about the possibilities and decided to move ahead.

How does this work? How are mRNA vaccines tailored to a person’s individual tumor?

After a patient’s pancreatic tumor is surgically removed, the tumor is genetically sequenced to look for the mutations that produce the best neoantigen proteins – that is, the neoantigens that are most aggressive to the immune system. Looks like a foreigner. The vaccine is produced with mRNA specific for these proteins in that person’s tumor. While the vaccine is being made, the patient receives a dose of the checkpoint inhibitor drug. We believe that checkpoint inhibitors may work in conjunction with these vaccines to boost the immune response to tumors.

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

In December 2019, we enrolled the first patients in a clinical trial to test whether this vaccine is safe. The process of making vaccines was challenging. For example, COVID-19 vaccines are not personalized – each vaccine is identical – so they are easier to make in large batches.

mRNA cancer vaccines must be individually tailored for each patient based on their tumor. To do this, we have to perform a very complex cancer surgery to take out the tumor, send the samples to Germany, sequence them, make the vaccine, and then send them back to New York – all within a short time frame. Thankfully, we were up to the task and met our goal of enrolling a total of 20 patients, almost a year ahead of schedule.

How did you manage to conduct clinical trials amid the pandemic?

When the pandemic began, we knew we needed to adapt quickly to ensure our patients were not affected. Thanks to our research team led by Christina Olsi, we coordinated very complex logistics to ensure that the trial ran smoothly. When we started, our estimated time to complete the trial was two and a half years. We completed it in 18 months.

This is due to the amazing leadership of Jeffrey Drebin, chair of the department of surgery, and William Jarnagin, chief of the hepatopancreatobiliary service. Dr. Drebin recognized the importance of this trial early on and has been one of the study’s strongest supporters, enrolling most of the patients himself. Medical oncologist Eileen O’Reilly, physician-scientist Jade Volchok, biologist Taha Merghoub, and computational biologist Ben Greenbaum were also invaluable in making the trial successful. We also received tremendous support for the study from the Stand Up 2 Cancer/Lustgarten Foundation, without which this study would not have been possible.

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

This shows that we are on the right track. An mRNA vaccine could trigger the production of T cells that recognize pancreatic cancer cells. It’s exciting to see how a personalized vaccine can activate the immune system to fight pancreatic cancer – which urgently needs better treatments – and other cancers.

What are the next steps for testing mRNA vaccines?

We will continue to analyze data from the trial so we can better understand what factors help the vaccine work in patients. We hope this information will be used to refine the vaccines so they are more effective and work in more people with pancreatic cancer. In this quest to improve the vaccine, we published new research in May 2022 Nature In which methods for selecting the best neonatal antigens were suggested.

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

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

This has been a great example of MSK’s visionary thinking in cancer care – to bring the most exciting medicines to cancer patients. With mRNA vaccines, we were working with them before they became popular to test our scientific discoveries in patients.

key takeaways

• Some people with pancreatic cancer survive for 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 other types of immunotherapy.

• Early results show that the vaccine is having the desired effect on the immune system.

For more science and technology stories check out our New Discoveries section bright side of news,

Note: The above content is provided by Memorial Sloan Kettering Cancer Center. Content can be edited for style and length.

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