When a routine scan led to American Barbara Brigham’s pancreatic cancer diagnosis in 2020, all she could think about was how she wanted more time – which a clinical trial involving an mRNA vaccine has since given her.
On diagnosis, she had turned to her care team at Memorial Sloan Kettering Cancer Centre to learn about her options. Brigham had first gone to the cancer centre when she was diagnosed with a small, non-cancerous cyst on her pancreas. Every year, she had a scan to make sure there were no new cysts. It was that annual scan that found the early-stage pancreatic cancer.
At Sloan-Kettering, she met Dr Vinod Balachandran, a surgical oncologist who specialises in pancreatic cancer. While laying out her options to fight the cancer, he mentioned that he was running a clinical trial for which he believed she would be the “perfect candidate”.
The trial would combine standard surgery and chemotherapy treatments – the standard of care for pancreatic cancer – with a customised mRNA vaccine. Each vaccine would be designed based on the patient's individual tumour.
The idea was that the vaccines could hopefully help the body’s immune system attack the cancer, Balachandran told CBS News.
“The prognosis was not good when I was diagnosed,” said Brigham. “You know you're going to have a limited amount of time. I just wanted to extend that time.”
Helping immune system recognise cancer
The inspiration for the clinical trial came from the small handful of long-term pancreatic survivors, Balachandran said. Only about 10% of people diagnosed with pancreatic cancer survive for more than five years.
About a decade ago, Balachandran and other researchers turned their attention to these “long-term” survivors. Multiple studies found that their immune systems generated spontaneous immune response to the cancer, meaning the immune system could recognise that the cancer was a threat and react accordingly.
“Typically, it’s challenging to teach the immune system to recognise cancer,” said Balachandran, “because it is hardwired not to recognise our own body.
“This led to this question of, ‘If this is what is happening in the best case scenario, could we then replicate the success in other pancreatic cancer patients?’ Namely, could we teach other patients’ immune systems to recognise their cancers in a very similar way as to what is happening naturally in the long-term survivors?”
The phase 1 clinical trial looked at 16 patients with early-stage pancreatic cancer like Brigham’s. To be eligible for the trial, a patient’s cancer had to only be in the pancreas and be removable with surgery.
Those conditions occur in just between 20% and 25% of pancreatic cancer patients, and mirrored the conditions of most long-term survivors.
During surgery, a patient’s tumour was removed, then sent to Sloan-Kettering’s research partners at German biotechnology company BioNTech. From the tumour, BioNTech would make the vaccine, which would be given to the patient alongside several weeks of immunotherapy and chemotherapy.
The vaccine targeted mutations created by pancreatic cancer. As cancer cells rapidly divide in the body, they accumulate genetic errors, Balachandran said. Those errors could serve as red flags to the immune system, he said, so it became a matter of alerting the immune system to those cells and teaching it to recognise them.
Sparking ‘strong immune responses’
Of the 16 patients included in the trial, eight had strong immune responses. The difference seemed to hinge on what kind of surgery they had to remove their pancreatic cancer:
“People who had their spleen removed as part of their treatment did not generate a strong immune response,” Balachandran added, “probably because of the important role the organ plays in immune function.”
Earlier data published by Balachandran showed that of the eight people who had strong immune responses, none had their cancer recur 18 months after treatment. On average, people whose early-stage pancreatic cancer is treated with chemotherapy and surgery see their cancer recur in a year or less.
Now, new research published in Nature looked at the same patients 3.2 years after their treatment. The follow-ups found that only two of the eight patients who had a strong immune response saw their cancer return.
Meanwhile, seven of the eight non-responding patients had their cancers return within that 3.2-year window, Balachandran said.
While the data seems promising, he cautioned that it’s “still hard to attribute causality” to the vaccine, especially because of the trial’s small size.
Dr Suneel Kamath, a gastrointestinal oncologist at Cleveland Clinic who was not involved with the trial, said the survival rate of the patients in the trial is similar to the survival rate of people who have early-stage pancreatic cancer treated with surgery and chemotherapy.
“This was a nice kind of proof-of-concept study to show that we can make a vaccine for this disease, and it really does actually create an immune response, and an immune response that lasts,” Kamath said. “That’s a very nice backbone to build off.”
Another, larger clinical trial is now under way, Balachandran said. This randomised trial will only focus on early-stage pancreatic cancer patients with intact spleens, to confirm what role that organ plays in the process. It will also help confirm if there is a link between the vaccines and better outcomes for pancreatic cancer patients.
mRNA vaccines as cancer treatment
Many other researchers are focusing on how mRNA vaccines could be used to treat cancer. Such research was under way well before the coronavirus pandemic thrust mRNA vaccination into the spotlight, said Kamath, who is working with Moderna on a different mRNA vaccine trial looking at pancreatic and gastric cancer.
Part of what makes mRNA vaccines suitable for cancer treatment is how easily they can be customised, Kamath said.
Balachandran said that it took about nine weeks for a vaccine to be made for each patient in the clinical trial. That included international shipping on both sides.
“The beauty of mRNA vaccines, as we saw with Covid development, is they’re very fast to make, easy to generate. Once you’ve found a new target, it’s very quick to make a vaccine for that particular target,” Kamath explained.
“It’s exciting, because when we talk about curing cancer, it’s not really a single monolithic disease. There are probably hundreds of different targets for every cancer type. And so the ability to make vaccines against a lot of those different targets very quickly is really powerful.”
Part of that research is learning which cancers are better candidates for mRNA vaccines to be used as part of the treatment, Kamath said.
Things like melanoma, which causes a lot of mutations in the body, are easier to direct the immune system against. Kidney and lung cancers are other promising options.
Something like pancreatic cancer, which has fewer mutations, is more difficult, but has been the subject of previous research.
Balachandran said part of his goal in looking at pancreatic cancer was to see if mRNA vaccines could make a difference “among the most challenging cancers in oncology”.
“Hopefully this can provide some important lessons and clues on how we can do this in other cancer types,” he added.
‘A wondrous thing’
For Brigham, participating in the clinical trial gave her what she wanted: more time with her family and loved ones – more than four years after she was diagnosed with pancreatic cancer. On average, for people whose pancreatic cancer is caught before the tumour grows much or spreads, survival time is about three to three and a half years, according to Johns Hopkins.
She has not had any recurrences since she took part in the trial. The removal of part of her pancreas did make her diabetic, because the organ produces insulin, but she says it’s manageable.
Study details
RNA neoantigen vaccines prime long-lived CD8+ T cells in pancreatic cancer
Zachary Sethna, Pablo Guasp, Vinod Balachandran et al.
Published in Nature on 19 February 2025
Abstract
A fundamental challenge for cancer vaccines is to generate long-lived functional T cells that are specific for tumour antigens. Here we find that mRNA–lipoplex vaccines against somatic mutation-derived neoantigens may solve this challenge in pancreatic ductal adenocarcinoma (PDAC), a lethal cancer with few mutations. At an extended 3.2-year median follow-up from a phase 1 trial of surgery, atezolizumab (PD-L1 inhibitory antibody), autogene cevumeran1 (individualised neoantigen vaccine with backbone-optimized uridine mRNA–lipoplex nanoparticles) and modified (m) FOLFIRINOX (chemotherapy) in patients with PDAC, we find that responders with vaccine-induced T cells (n = 8) have prolonged recurrence-free survival (RFS; median not reached) compared with non-responders without vaccine-induced T cells (n = 8; median RFS 13.4 months; P = 0.007). In responders, autogene cevumeran induces CD8+ T cell clones with an average estimated lifespan of 7.7 years (range 1.5 to roughly 100 years), with approximately 20% of clones having latent multi-decade lifespans that may outlive hosts. Eighty-six percent of clones per patient persist at substantial frequencies approximately 3 years post-vaccination, including clones with high avidity to PDAC neoepitopes. Using PhenoTrack, a novel computational strategy to trace single T cell phenotypes, we uncover that vaccine-induced clones are undetectable in pre-vaccination tissues, and assume a cytotoxic, tissue-resident memory-like T cell state up to three years post-vaccination with preserved neoantigen-specific effector function. Two responders recurred and evidenced fewer vaccine-induced T cells. Furthermore, recurrent PDACs were pruned of vaccine-targeted cancer clones. Thus, in PDAC, autogene cevumeran induces de novo CD8+ T cells with multiyear longevity, substantial magnitude and durable effector functions that may delay PDAC recurrence. Adjuvant mRNA–lipoplex neoantigen vaccines may thus solve a pivotal obstacle for cancer vaccination.
See more from MedicalBrief archives:
Small pancreatic cancer vaccine trial shows promise
mRNA vaccine can recognise neoantigens in pancreatic cancers – US study
Cancer: Survivability is changing fast
Personalised mRNA jab a ‘game-changer’ for cancer patients