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 autogene cevumeran continues to show potential to stimulate an immune response that may reduce the risk of the disease returning after surgery in a small patient group.
New results from the phase 1 clinical trial, now published in the journal Nature, show that the therapeutic cancer vaccine activated tumor-specific immune cells that persisted in the body up to nearly four years after treatment in some patients. In addition, patients with a vaccine-induced immune response had a reduced risk of the cancer coming back at a three-year follow-up compared with patients whose immune systems did not respond.
“The latest data from the phase 1 trial are encouraging,” says Vinod Balachandran, MD, principal investigator of the trial and senior author of the new publication. “They suggest this investigational therapeutic mRNA vaccine can mobilize anti-tumor T cells that may recognize pancreatic cancers as foreign, potentially years after vaccination.”
Dr. Balachandran is a pancreatic cancer surgeon-scientist in the Human Oncology and Pathogenesis Program and Director of The Olayan Center for Cancer Vaccines (OCCV) at Memorial Sloan Kettering Cancer Center (MSK). The OCCV is a research hub that spans the full spectrum of basic discovery to clinical application of cancer vaccines.
The phase 1 study tested autogene cevumeran (BNT122, RO7198457), a therapeutic mRNA cancer vaccine developed and researched through a collaboration between BioNTech, an immunotherapy company, and Genentech, a member of the Roche Group.
The therapeutic mRNA cancer vaccine was personalized for each of the 16 participants in the trial based on the mutational profile of each patient’s tumor. As reported in 2023 in Nature, the vaccine was safe with no serious side effects and stimulated an immune response in half of patients.
Therapeutic cancer vaccines such as autogene cevumeran are designed to treat — not prevent — cancer. By delivering proteins found exclusively in cancer (called neoantigens), these vaccines aim to train the immune system to recognize cancer cells as foreign.
Therapeutic cancer vaccines that can stimulate a robust, long-lived immune response with clinical impact have remained largely elusive. But recent research and technological developments in mRNA technology are changing the field. This approach is primarily aimed at the early stages of cancer, where the cancer has not yet spread and tumors can be surgically removed, to help delay or prevent recurrence.
In these findings from the phase 1 trial, the researchers could detect vaccine-stimulated T cells at substantial frequencies up to nearly four years after treatment. The team was able to track the vaccine-induced T cells with the help of computational biologist Benjamin Greenbaum, PhD.
The vaccine-stimulated T cells retained their anti-cancer activity, even after patients received chemotherapy following initial doses of the vaccine. Researchers had wondered whether chemotherapy might somehow diminish the effects of the vaccine. It did not seem to in this small, early study.
“For patients with pancreatic cancer, our latest results continue to support the approach of using personalized mRNA vaccines to target neoantigens in each patient’s tumor,” Dr. Balachandran says. “If you can do this in pancreas cancer, theoretically you may be able to develop therapeutic vaccines for other cancer types.”
Pancreatic cancer is one of the deadliest cancers, even for patients whose tumors are removed with surgery. Only about 13% of patients are alive five years after diagnosis, according to the American Cancer Society. 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.
Dr. Balachandran’s team in the OCCV aims to innovate next-generation cancer vaccines, with initial goals to expand vaccine use in pancreatic and other cancers lacking effective treatments.
New Clinical Trial Results for mRNA Pancreatic Cancer Vaccine
The investigator-initiated, single-center phase 1 clinical trial involved studying 16 MSK patients who received the investigational therapeutic cancer vaccine autogene cevumeran, along with an immunotherapy drug called atezolizumab and a chemotherapy regimen called mFOLFIRINOX. Early immunological and clinical results from the trial published in Nature in 2023 showed this treatment was generally well tolerated and stimulated an immune response that correlated with delayed recurrence at a 1.5-year median follow-up compared with non-responders.
Results at a three-year median follow-up, now published, show:
- The investigational cancer vaccine activated a T cell response in half of patients (responders), and this response correlated with delayed recurrence at three-year post-treatment follow-up compared with non-responders. Researchers do not yet know if the vaccine caused the delay in cancer recurrence; investigating this question is a goal of an ongoing randomized phase 2 clinical trial.
- Of the eight patients whose immune systems responded to the vaccine during the study period, six have not seen their cancers return during the follow-up period. The other two patients relapsed. These patients with relapse showed weaker vaccine-induced T cell activity compared with other responders.
- By studying tissue and blood from these patients before and after the vaccine was given, the team found that the majority of T cells had been newly stimulated by the vaccine, as these T cells were undetectable before vaccination. In addition, the majority of these vaccine-induced T cells persisted beyond two years post-vaccination and maintained anti-cancer function in some patients.
Phase 2 Trial Is Ongoing To Evaluate the mRNA Vaccine Candidate in a Larger Patient Group
A phase 2 clinical trial, sponsored by Genentech in collaboration with BioNTech, is evaluating 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 data from our phase 1 trial, we are excited to evaluate therapeutic mRNA cancer vaccines in more pancreatic cancer patients,” Dr. Balachandran says.
The phase 2 trial will study whether the mRNA vaccine 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 an immunotherapy drug called a checkpoint inhibitor, autogene cevumeran, 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 vaccine will be personalized for each patient’s tumor 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, Director of The Olayan Center for Cancer Vaccines at MSK, explains how this new approach is being developed aiming 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 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 try to instruct cells in your body to make a protein that may 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 investigational vaccines that may help the immune system to tell the difference.
This builds on important work done at MSK that has shown how critical tumor mutations are to trigger 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. The individualized therapeutic mRNA cancer vaccine must be personalized 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 and other trial centers where the investigational treatment is researched.
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 may cause immune cells called dendritic cells to make the neoantigen proteins. And in some cases, the dendritic cells also may 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 trying to advance research on these investigational cancer mRNA vaccines?
We at MSK are continuing to examine if vaccine-induced T cells last and remain functional long-term and how these features associate with patient outcomes. We have established a robust platform in The Olayan Center for Cancer Vaccines at MSK that allows us to discover and test new vaccine concepts in pancreatic and other deadly cancers.
This story was originally posted in July 2023 and has been updated.
