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Dr. Vinod Balachandran says mRNA vaccines could stimulate the immune system to recognize and attack pancreatic cancer cells.
A new approach to treating pancreatic cancer is progressing to the next step in making it available to more patients. After results from a small study, a phase 2 clinical trial has now opened to test the effectiveness of using an mRNA vaccine to fight one of the deadliest cancers.
The new trial is investigating whether this therapeutic vaccine reduces the risk of pancreatic cancer returning after the tumor is removed by surgery. The study will enroll approximately 260 patients at Memorial Sloan Kettering Cancer Center (MSK) and nearly 80 sites around the world.
The trial is open to people newly diagnosed with pancreatic cancer who have not yet had surgery or other treatment (such as chemotherapy, immunotherapy, or radiation therapy) and who fit other specific criteria.
The mRNA vaccines are custom-made for every person. They use proteins in the pancreatic tumors, called neoantigens, to alert the immune system that the cancer cells are foreign. In this way, the mRNA vaccine trains the body to protect itself against cancer cells.
The phase 2 trial follows results from a phase 1 trial involving 16 MSK patients, reported May 10, 2023, in Nature. The vaccine may have prevented or delayed relapses in about half the patients who received it.
“We are excited to test personalized mRNA vaccines in more pancreatic cancer patients,” says MSK pancreatic cancer surgeon-scientist Vinod Balachandran, MD. Dr. Balachandran led the phase 1 trial in collaboration with Genentech, a member of the Roche Group, and BioNTech, an immunotherapy company.
The phase 2 trial will test whether the mRNA approach works better than the current standard treatment. Patients will be randomly split into two groups:
The phase 1 trial suggested that the mRNA vaccines are safe and cause an effective and lasting immune response:
“The evidence from the phase 1 trial showed that we are on the right track: An mRNA vaccine can trigger T cells to recognize pancreatic cancers as foreign,” Dr. Balachandran says. “Moreover, the vaccines stimulated many such T cells, and we continued to detect T cells stimulated by such vaccines in patients up to two years later. It supported our strategy to tailor each vaccine to each patient’s tumor.
Here, Dr. Balachandran explains how this new approach has been developed to treat one of the deadliest cancers — using the same mRNA vaccine technology that created the COVID-19 vaccine. It all began with a discovery in his lab about pancreatic cancer and a global collaboration with Genentech and BioNTech in the middle of the COVID-19 pandemic.
There has been great interest in using immunotherapy for pancreatic cancer because nothing else has worked very well. We thought immunotherapy held promise because of research we began about eight years ago. A small subset of patients with pancreatic cancer manage to beat the odds and survive after their tumor is removed. We looked at the tumors taken from these select patients and saw that the tumors had an especially large number of immune cells in them, especially T cells. Something in the tumor cells seemed to be sending out 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, triggering the immune system attack. When tumor cells divide, they accumulate these neoantigens, which are caused by genetic mutations. 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 threats. But in our study, we saw that neoantigens in the pancreatic cancer survivors were different — they did not escape notice. They, in effect, uncloaked the tumors to T cells, causing the T cells to recognize them.
We found that T cells recognizing these neoantigens circulated in the blood of these rare patients for up to 12 years after the pancreatic tumors had been removed by surgery. The T cells had memory of the neoantigens as a threat.
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 as vaccines. We were particularly interested in mRNA vaccines, a new technology that we thought was quite promising. The 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, BioNTech co-founder and CEO Uğur Şahin emailed us that he had read our paper and was interested in our ideas. He and his team were working with Genentech on individualized neoantigen-based mRNA therapies. In late 2017, we flew to Mainz, Germany, where BioNTech is based. Of course, BioNTech is famous now for its work in developing a vaccine against COVID-19, but they were still a little-known company at that point. We had dinner with Uğur and his team in Mainz as well as with Ira Mellman from Genentech. We discussed the potential of mRNA vaccines for pancreatic cancer — as well as the possible use of the mRNA platform they have developed.
Designing a cancer vaccine tailored to an individual is complex. Because cancers arise from our own cells, it is much harder for the immune system to distinguish proteins in cancer cells as foreign compared with proteins in pathogens like viruses. But important advances in cancer biology and genomic sequencing now make it possible to design vaccines that can tell the difference.
This builds on important work done at MSK that has shown how critical tumor mutations are to triggering an immune response. In parallel with our work, major discoveries in mRNA technology over the past decades by scientists such as Dr. Sahin and BioNTech co-founder Özlem Türeci paved the way to use mRNA in medicine. We all felt optimistic about the potential and decided to move ahead.
After a patient has a pancreatic tumor surgically removed, the tumor is genetically sequenced to look for mutations that produce the best neoantigen proteins — those that look the most foreign to the immune system. The vaccine is manufactured with mRNA specific to these proteins in that individual’s tumor.
The process to make personalized vaccines for cancer treatment is more complex than making a preventive vaccine for an infectious disease, where each vaccine is the same and can be manufactured in large batches. An individualized therapeutic mRNA cancer vaccine must be tailored to each patient’s tumor. To do this, we had to perform a very complex cancer surgery to take out the tumor and ship the sample to BioNTech in Germany. They sequence the tumor and make the vaccine, which is then sent back to New York.
The vaccine is infused into a person’s bloodstream. In some patients it can cause immune cells called dendritic cells to make the neoantigen proteins. And in some cases, the dendritic cells also train the rest of the immune system, including T cells, to recognize and attack tumor cells that express these same proteins. With the T cells on high alert to destroy cells bearing these proteins, the cancer may have a lower chance of returning.
The data gathered from the phase 2 trial will be analyzed to better understand what factors help the vaccine work in patients. Of course, we want to find out why some patients with pancreatic cancer don’t respond to the vaccine and find solutions to this problem. In this quest to make the vaccine better, we published research in May 2022 that suggested ways to choose the best neoantigens, which we will continue to incorporate going forward.
It’s exciting to see that a personalized vaccine could enlist the immune system to fight pancreatic cancer. Our longer-term hope is that we may be able to use such personalized vaccines to treat other deadly cancers.
All this progress has depended on a significant philanthropic commitment, and the generosity of donors will enable us to continue making rapid strides forward. We received tremendous support for the study from the Stand Up To Cancer organization, the Lustgarten Foundation, the Ben and Rose Cole Charitable PRIA Foundation, and the Damon Runyon Cancer Research Foundation, without which this study would not have been possible.
I also want to thank the leadership of our Department of Surgery Chair Jeffrey Drebin, MD, and Hepatopancreatobiliary Service Chief William Jarnagin, MD. Dr. Drebin recognized the importance of this trial early on and has been the strongest proponent of the study, enrolling most of the patients himself.
Medical oncologist Eileen O’Reilly, MD; computational biologist Ben Greenbaum, PhD; physician-scientist Jedd Wolchok, MD; and biologist Taha Merghoub, PhD, were also invaluable in pushing to make this trial happen.
This story was originally posted in July 2023 and has been updated.
The research reported in Nature was supported by a Stand Up To Cancer Convergence Award, the Lustgarten Foundation, the NIH U01 CA224175 Pancreatic Cancer Microenvironment Network Cancer Moonshot Award, the Damon Runyon Clinical Investigator Award, the Ben and Rose Cole Charitable PRIA Foundation, the Mark Foundation ASPIRE Award, and the Pershing Square Sohn Prize-Mark Foundation Fellowship. Services of the Integrated Genomics Core were funded by the NCI Cancer Center Support Grant, Cycle for Survival, and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology. The team at MSK sponsored the phase 1 clinical trial. The imCORE Network, Genentech, BioNTech, Stand Up To Cancer, the Lustgarten Foundation, and the National Cancer Institute Pancreatic Cancer Microenvironment Network funded the phase 1 clinical trial and the biomarker studies. The phase 2 trial is sponsored by Genentech.
Vinod P. Balachandran discloses the following relationships and financial interests:
Eli Lilly and Company
Provision of Services (uncompensated)
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