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dated: 2022-11-19 03:16:51 .
[Nov 18, 2022: Vinod P. Balachandran, Memorial Sloan Kettering Cancer Center]
The key to these vaccines appears to be proteins in pancreatic tumors, called neoantigens, that alert the immune system to prevent cancer. (PHOTO: Creative Commons)
Messenger RNA (mRNA) vaccines may be the hottest thing in science right 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 working on using mRNA vaccine technology to treat cancer.
Vinod Balachandran, a physician and 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 an mRNA vaccine for pancreatic cancer. The key to these vaccines appears to be proteins in pancreatic tumors, called neoantigens, that alert the immune system to prevent cancer.
Vaccines are made individually for each person. The hope is that the vaccine will stimulate the production of certain immune cells called T cells, which recognize pancreatic cancer cells. This could reduce the risk of the cancer returning after the main tumor has been surgically removed.
In 8 of the 16 patients tested, the vaccines activated T cells, which recognize the patient’s own pancreatic cancer. These patients also showed delayed recurrence of pancreatic cancer, suggesting that vaccine-activated T-cells may have the desired effect in suppressing pancreatic cancer.
Dr. Balachandran explains how a collaboration with BioNTech — which developed the Pfizer-BioNTech vaccine against COVID-19 — led to this potential treatment for pancreatic cancer.
What was the inspiration for using the pancreatic cancer vaccine?
There is a lot of interest in using immunotherapy for pancreatic cancer because nothing else has worked very well. We thought immunotherapy was promising because we started the research about seven years ago. A small subset of pancreatic cancer patients manage to beat the odds and survive after tumor removal. We looked at the tumors of these selected patients and found that the tumors contained particularly high numbers of immune cells, especially T cells. Something in the tumor cells seemed to send a signal that alerted and attracted the T-cells.
We later discovered that these signals were proteins called neoantigens, which T cells recognize as foreign and trigger an immune system attack. Tumor cells accumulate these neoantigens through genetic mutations as they divide. In most people with pancreatic cancer, the immune cells do not recognize these neoantigens, 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. They actually exposed the tumors to the T-cells, causing the T-cells to recognize them.
Even more amazingly, T cells recognizing these neoantigens circulated in the blood of these rare patients for up to 12 years after surgical removal of the pancreatic tumor. This sustained immune response was like auto-vaccination. T-cells had memory of neoantigens as a threat, much like vaccines trigger memory and protect against pathogens for decades. The discovery led us to speculate that artificially inducing this effect might be effective in other pancreatic cancer patients.
How could an mRNA vaccine work against pancreatic cancer?
My colleagues and I published our findings on immune protection in long-term pancreatic cancer survivors in the journal Nature in November 2017. While we were working on this, we were also looking for ways to deliver neoantigens to patients as vaccines. We were particularly interested in mRNA vaccines, a new technology that we thought showed great promise. Vaccines use mRNA, part of the genetic code, to teach cells in your body to make a protein that triggers an immune response.
Coincidentally, at this point, BioNTech co-founder and CEO Uğur Şahin sent us an email saying that he had read our work and was interested in our ideas. At the end of 2017, we flew to Mainz, Germany, where BioNTech is headquartered. At that time, they were still a little-known company. We had dinner with Uğur 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.
Developing an effective cancer vaccine is difficult. Because cancer arises from our own cells, it is much more difficult for the immune system to distinguish proteins in cancer cells as foreign than proteins in pathogens such as viruses. But major advances in cancer biology and genome sequencing now allow the design of vaccines that can tell the difference. This builds on important work by MSK, which has shown how key tumor mutations are in triggering an immune response. We were all optimistic about the potential and decided to move on.
How does it work? How is the mRNA vaccine tailored to a person’s individual tumor?
After a patient’s pancreatic tumor is surgically removed, the tumor is genetically sequenced 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 those proteins in that person’s tumor. While the vaccine is being made, the patient is given a single dose of a drug that is a checkpoint inhibitor. We believe that checkpoint inhibitors may work together with these vaccines to enhance the immune response against tumors.
When an mRNA vaccine is injected into a person’s bloodstream, it triggers immune cells called dendritic cells to make 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. When T cells are on standby to destroy cells that carry these proteins, the cancer may be less likely to return.
In December 2019, we enrolled the first patient in a clinical trial to test the safety of this vaccine. The process of making the vaccine was demanding. For example, vaccines against COVID-19 are not personalized – every vaccine is the same – so they are easy to mass produce.
The MRNA cancer vaccine must be made individually for each patient based on their tumor. To do this, we have to perform a very complex cancer operation to remove the tumor, send the sample to Germany, sequence it, make the vaccine and then send it back to New York – all on short notice. Fortunately, we were up to the task and completed the enrollment of our target total of 20 patients almost a year ahead of schedule.
How did you manage to conduct a clinical study in the middle of a pandemic?
When the pandemic started, we knew we had to adapt quickly to make sure our patients weren’t affected. Thanks to our research team, led by Cristina Olcese, we were able to coordinate very complicated logistics to ensure the study ran smoothly. When we started, the estimated time to complete the studies was two and a half years. We finished it in 18 months.
This is due to the great leadership of the Chair of the Department of Surgery, Jeffrey Drebin, and the Chief of the Hepatopancreatobiliary Service, William Jarnagin. dr. Drebin recognized the importance of this study early on and was its biggest supporter, enrolling most of the patients himself. Medical oncologist Eileen O’Reilly, physician and scientist Jedd Wolchok, biologist Taha Merghoub, and computational biologist Ben Greenbaum were also invaluable in conducting this study. We also received great 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. The MRNA vaccine can stimulate the production of T cells that recognize pancreatic cancer cells. It is very exciting to see that a personalized vaccine could stimulate the immune system to fight pancreatic cancer – which is in desperate need of better treatments – as well as other cancers.
What are the next steps for mRNA vaccine testing?
We will continue to analyze data from the study so we can better understand what factors help the vaccine work in patients. We hope to use this information to improve the vaccine so that it is more effective and works for more people with pancreatic cancer. In our effort to improve the vaccine, we published new research in May 2022 Nature proposed options for selecting the best neoantigens.
Our team here at MSK is fantastic, as are the teams at BioNTech and Genentech who funded the study. We will continue with a larger study to test the personalized mRNA vaccine in more pancreatic cancer patients.
According to Vinod Balachandran, mRNA vaccines can stimulate the immune system to recognize and attack pancreatic cancer cells. (PHOTO: Memorial Sloan Kettering Cancer Center)
This was an excellent example of MSK’s forward-thinking vision in cancer care – to bring the most exciting medicines to cancer patients. We worked with mRNA vaccines before they became popular to test our scientific discoveries on patients.
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 another type of immunotherapy.
The first results show that the vaccine has the desired effect on the immune system.
For more science and technology stories, check out our New Discoveries section at The brighter side of the news.
Note: The above materials were provided by Memorial Sloan Kettering Cancer Center. Content can be edited for style and length.
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Study shows mRNA vaccine can stop pancreatic cancer
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