How could an mRNA vaccine 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 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 cofounder and CEO Uğur Şahin 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 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, who was 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. Because cancer arises 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 immune response. We all felt optimistic about the potential and decided to move 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 look the most foreign to the immune system. The vaccine is manufactured with mRNA specific to these proteins in that individual’s tumor. While the vaccine is being made, the patient gets a single dose of a checkpoint inhibitor drug. We think checkpoint inhibitors can work in conjunction with these vaccines to boost immune responses to tumors.
When the mRNA vaccine is injected into a person’s bloodstream, it causes immune cells called dendritic cells to make the neoantigen proteins. 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.
In December 2019, we enrolled the first patient in a clinical trial to test if this vaccine was safe. The process to make the vaccines was challenging. For example, the COVID-19 vaccines are not personalized — each vaccine is the same — so it is easy to make them in large batches. The mRNA cancer vaccine must be made individually for each patient based on their tumor. To do this, we must perform a very complex cancer surgery to take out the tumor, ship the sample to Germany, have them sequence it, make the vaccine, and then send back to New York — all within a short timeframe. Thankfully, we were up to the task and just finished enrolling our target total of 20 patients nearly a year ahead of schedule. If all goes well, we plan to conduct larger studies in the future to test mRNA vaccines in cancer patients.
How did you manage to conduct the clinical trial in the middle of a pandemic?
Our team here is fantastic, and so are the teams at BioNTech and at Genentech, which funded the study. When the pandemic began, we knew we needed to adapt quickly to make sure our patients were not affected. Thanks to our research team, led by Cristina Olcese, we coordinated very complicated logistics to make sure the trial ran smoothly for our patients.
When we started, our estimated time to complete the trial was two and a half years. We finished it in 18 months. That’s due to the amazing leadership of Department of Surgery Chair Jeffrey Drebin, and Hepatopancreatobiliary Service Chief William Jarnagin. Dr. Drebin recognized the importance of this trial early on and has been the strongest proponent of the study, enrolling the majority of the patients himself. Medical oncologist Eileen O’Reilly, physician-scientist Jedd Wolchok, biologist Taha Merghoub, and computational biologist Ben Greenbaum were also invaluable in pushing to make this trial happen. 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. This has been 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 were working with them before they were popular to test our scientific discoveries in patients.
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