[Jan. 18, 2023: 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 keep the cancer at bay. (PHOTO CREDIT: Creative Commons)
Messenger RNA (mRNA) vaccines may be the hottest thing in science right now, as they have helped reverse COVID-19. But even before the pandemic began, researchers at Memorial Sloan Kettering Cancer Center were working to use 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 mRNA vaccines for pancreatic cancer. The key to these vaccines appears to be proteins in pancreatic tumors, called neoantigens, that alert the immune system to keep the 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, which recognize pancreatic cancer cells. This can reduce the risk of the cancer coming back after the main tumor has been removed by surgery.
In 8 out of 16 patients studied, the vaccines activated T cells, which recognize the patient’s own pancreatic cancer. These patients also showed a delayed recurrence of their pancreatic cancer, suggesting that the T cells activated by the vaccines may be having the desired effect of keeping the pancreatic cancer at bay.
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Dr. Balachandran explains how a collaboration with BioNTech — which developed the Pfizer-BioNTech COVID-19 vaccine — led to this potential pancreatic cancer treatment.
What was the inspiration for using a pancreatic cancer vaccine?
There is a lot of interest in using immunotherapy for pancreatic cancer as nothing else has worked very well. We thought that immunotherapy had promise because we started the research about seven years ago. A small subset of pancreatic cancer patients manage to beat the odds and live after their tumor is removed. We looked at the tumors of these selected patients and found that the tumors contain a particularly large number of immune cells, especially T cells. Something in the tumor cells seemed to be sending a warning signal and attracted the T cells.
We later found that these signals were proteins called neoantigens, which the T cells recognize as foreign and cause the immune system to attack. Tumor cells accumulate these neoantigens through genetic mutations as they divide. In most people with pancreatic cancer, these neoantigens are not recognized by the 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 escape attention. They actually exposed the tumors to the T cells, causing the T cells to recognize them.
More impressively, T cells that recognize these neoantigens circulate in the blood of these rare patients up to 12 years after the surgical removal of pancreatic tumors. This sustained immune response was like auto-vaccination. The T cells had memory of the neoantigens as a threat, similar to how vaccines induce memory and protect against pathogens for decades. The finding led us to speculate that the artificial induction of this effect could be effective in other patients with pancreatic cancer.
How might an mRNA vaccine work against pancreatic cancer?
My colleagues and I published our findings on immune protection in long-term pancreatic cancer survivors in Nature in November 2017. While we were working on this, we also looked at ways to deliver neoantigens to patients as vaccines. We were particularly interested in mRNA vaccines, a new technology that we thought held 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.
By chance, at this point, BioNTech co-founder and CEO Uğur Şahin emailed us that he had read our paper and was interested in our ideas. At the end of 2017 we flew to Mainz, Germany, where BioNTech is based. 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 worked 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 are now making it possible to design vaccines that can tell the difference. This builds on important work by MSK, which has shown how crucial tumor mutations are to eliciting an immune response. We were all optimistic about the potential and decided to go ahead.
How does it work? How is the mRNA vaccine tailored to a person’s individual tumor?
After a patient has a pancreatic tumor surgically removed, the tumor is genetically sequenced to look for mutations that produce the best neoantigen proteins – that is, the neoantigens that appear most foreign to the immune system. The vaccine is made with specific mRNA for these proteins in that person’s tumor. While the vaccine is being made, the patient is given a single dose of a checkpoint inhibitor drug. We believe that checkpoint inhibitors can work together with these vaccines to enhance the immune response against tumors.
When the mRNA vaccine is injected into a person’s blood, it triggers immune cells called dendritic cells to make neoantigen 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 high alert 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 grafts was challenging. For example, the COVID-19 vaccines are not personalized – every vaccine is the same – so it is easy to mass produce them.
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, have it sequenced, make the vaccine and then send it back to New York – all in a short time. 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 the clinical study in the middle of a pandemic?
When the pandemic started, we knew we had to adapt quickly to ensure that our patients were not affected. Thanks to our research team, led by Cristina Olcese, we were able to coordinate very complicated logistics to ensure the smooth conduct of the study. When we started, our estimated time to complete the study was two and a half years. He completed it in 18 months.
This is due to the great leadership of the President of the Department of Surgery, Jeffrey Drebin, and the Head of the Hepatopancreatobiliary Service, William Jarnagin. Dr. Drebin recognized the importance of this study early on and was the strongest supporter of the study, enrolling the majority of 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?
It shows that we are on the right track. An mRNA vaccine can lead to the production of T cells that recognize pancreatic cancer cells. It is very exciting to see that a personalized vaccine can encourage the immune system to fight pancreatic cancer – which desperately needs better treatments – and other cancers as well.
What are the next steps for mRNA vaccine testing?
We will continue to analyze the data from the study so that we can better understand what factors help the vaccine work in patients. We hope to use this information to refine the vaccines so that they are more effective and work in more people with pancreatic cancer. In our quest to improve the vaccine, we published new research in May 2022 Nature suggested the options for choosing the best neoantigens.
Our team here at MSK is fantastic, as are the teams at BioNTech and Genentech who funded the study. We will proceed with a larger study to test the personalized mRNA vaccines in more pancreatic cancer patients.
According to Vinod Balachandran, mRNA vaccines can stimulate the immune system to recognize and attack pancreatic cancer cells. (PHOTO CREDIT: Memorial Sloan Kettering Cancer Center)
This was a great example of MSK’s forward-thinking vision in cancer care – to bring the most exciting medicines to cancer patients. With mRNA vaccines, we worked with them before they became popular to test our scientific discoveries on patients.
The central theses
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Some people with pancreatic cancer live many years after diagnosis.
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In these patients, the immune system prevents the cancer from coming back.
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A messenger RNA vaccine based on this concept is being tested along with another type of immunotherapy.
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Initial results indicate 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 lighter side of the news.
Note: Materials provided above by Memorial Sloan Kettering Cancer Center. Content can be edited for style and length.
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