Dr. Vinod Balachandran says mRNA vaccines could stimulate the immune system to recognize and attack pancreatic cancer cells.
An experimental approach to treating pancreatic cancer with the messenger RNA (mRNA)-based therapeutic cancer vaccine candidate autogene cevumeran continues to show potential to stimulate an immune response that may reduce the risk of the disease returning after surgery.
New results from a phase 1 clinical trial show that the cancer vaccine candidate activated immune cells that persisted in the body up to three years after treatment in certain patients. In addition, a vaccine-induced immune response correlated with reduced risk of the cancer coming back.
“The latest data from the phase 1 trial show that we are on the right track. This investigational mRNA vaccine can trigger T cells — the cells that mobilize anti-tumor immune responses — that may recognize pancreatic cancers as foreign,” says Memorial Sloan Kettering Cancer Center (MSK) pancreatic cancer surgeon-scientist Vinod Balachandran, MD. “Moreover, we continue to detect vaccine-stimulated T cells at substantial frequencies in patients’ blood up to three years after vaccination.”
Autogene cevumeran (BNT122, RO7198457) was developed through a collaboration between BioNTech, an immunotherapy company, and Genentech, a member of the Roche Group. Dr. Balachandran, who led the phase 1 trial, presented the latest results at the American Association for Cancer Research Annual Meeting in San Diego.
Pancreatic cancer is one of the deadliest cancers, and even with surgery, only about 12% of patients are alive five years after diagnosis. Chemotherapy, radiation, targeted therapy, and current immunotherapies are also largely ineffective against pancreatic cancer, so new therapies are urgently needed for patients who face this disease.
The investigational mRNA cancer vaccines were custom-made for every participant in the phase 1 clinical trial based on the mutational profile of each individual tumor. The cancer vaccines teach T cells to recognize proteins called neoantigens that are found exclusively in each patient’s pancreatic tumor. In this way, these vaccines alert the immune system that the cancer cells are foreign. The goal of this approach is to train the body to protect itself against cancer cells.
Initial results from the phase 1 trial, reported May 2023 in Nature, showed the vaccine was well tolerated and that it activated immune cells in half of treated patients. The latest results are based on following patients for a median of three years after the investigational treatment. The team was able to track vaccine-induced T cells with the help of computational biologist Benjamin Greenbaum, PhD.
“Our findings thus far show that this vaccine candidate can induce a lasting immune response — up to three years — in some patients,” explains Dr. Balachandran, a member of the Human Oncology and Pathogenesis Program and the David M. Rubenstein Center for Pancreatic Cancer Research at MSK. “As these are critical features of an effective cancer vaccine, the results continue to support the approach of using customized mRNA vaccines to target neoantigens in each patient’s tumor.”
New Clinical Trial Results for mRNA Pancreatic Cancer Vaccine Candidate
The investigator-initiated, single-center trial involved studying 16 MSK patients who received autogene cevumeran, along with an immunotherapy drug called atezolizumab and a chemotherapy regimen called mFOLFIRINOX. At the three-year median follow-up:
- In 8 patients, the investigational cancer vaccine activated a T cell response, and 6 of these patients had not seen their cancers return during the follow-up window. The other 2 patients relapsed. Meanwhile, cancer returned in 7 of the 8 patients whose immune systems did not respond to the vaccine during the study period. Researchers do not yet know if the vaccines caused the delay in cancer recurrence; investigating this question is a goal of an ongoing randomized phase 2 clinical trial.
- In the 8 patients who responded, the vaccines induced T cells specific to vaccine-encoded neoantigens. By studying tissue and blood from these patients before and after vaccines were given, the team found that 98% of the T cells specifically activated by the cancer vaccines were not present before vaccination. In addition, more than 80% of the vaccine-induced T cells persisted from two to up to three years after treatment. These data suggest the investigational cancer vaccine stimulated a durable T cell response.
Phase 2 Trial Is Ongoing To Evaluate the RNA Vaccine Candidate in a Larger Patient Group
A phase 2 clinical trial (NCT05968326), sponsored by Genentech in collaboration with BioNTech, will evaluate the efficacy and safety of autogene cevumeran in a larger patient group. The new study, which began in July 2023, will enroll approximately 260 patients at various sites around the world, including MSK.
“Given the positive data from our phase 1 trial, we are excited to evaluate individualized mRNA cancer vaccine candidates in more pancreatic cancer patients,” Dr. Balachandran says.
The phase 2 trial will study whether the mRNA approach works better than the current standard treatment. Patients will be randomly split into two groups:
- One group will receive standard treatment, which is surgery followed by chemotherapy. This will be the control group.
- The other group will receive the experimental treatment, which is surgery followed by autogene cevumeran (mRNA vaccine), an immunotherapy drug called a checkpoint inhibitor, and chemotherapy. (The phase 1 study followed a similar treatment plan but did not have a control group receiving standard treatment for comparison.)
- The mRNA vaccines will be custom-made for each patient and given in two phases: Doses at the beginning of treatment prime the immune system, and later doses provide a boost.
The trial is open to people with newly diagnosed pancreatic cancer eligible for surgery, who have not had other treatment (such as chemotherapy, immunotherapy, or radiation therapy) and who fit other specific criteria.
The Story of the mRNA Cancer Vaccine Study in Pancreatic Cancer
Here, Dr. Balachandran explains how this new approach has been developed to treat one of the deadliest cancers. It all began with discoveries in his lab about pancreatic cancer and a global collaboration with Genentech and BioNTech in the middle of the COVID-19 pandemic.
What was the inspiration for using a vaccine against pancreatic cancer?
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.
What causes the protective T cell response?
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 long-term 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.
How did the neoantigen discovery lead to a pancreatic cancer vaccine?
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 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, MD, 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 immunotherapies. In late 2017, we flew to Mainz, Germany, where BioNTech is based. We discussed the potential of therapeutic mRNA cancer vaccines for pancreatic cancer — as well as the possible use of the mRNA platform they have developed.
What makes creating an individualized cancer vaccine challenging?
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, the development of novel biotechnologies, 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 professor Şahin and BioNTech co-founder and Chief Medical Officer Özlem Türeci, MD, paved the way to use mRNA in medicine. We all felt optimistic about the potential and decided to move ahead.
How is the investigational mRNA pancreatic cancer vaccine made? How is it tailored to each individual tumor?
After a patient has a pancreatic tumor surgically removed, the tumor is genetically sequenced to look for up to 20 mutations that have the highest likelihood to produce the best neoantigens — those that look the most foreign to the immune system. The cancer vaccine candidate is manufactured with mRNA specific to these neoantigens found in that individual’s tumor.
The process to design and manufacture individualized 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 take a sample of the tumor that is removed during the required cancer surgery and ship the sample to BioNTech in Germany. They analyze the tumor sample, and design and manufacture the cancer vaccine candidate, which is then sent back to New York.
How is the mRNA vaccine given to patients? How does it trigger the immune response?
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.
How are you working to make the cancer mRNA vaccines more effective?
In patients treated in the phase 1 study, we are continuing to examine if vaccine-induced T cells last and remain functional long-term and how these features associate with patient outcomes.
This story was originally posted in July 2023 and has been updated.
