CANCER VACCINATION offers the promise of training the body’s immune system to identify and attack cancer cells from within. While this technology is one of the most exciting topics in cancer research, many investigational vaccines have not been effective in human trials.

But in the past decade, researchers have learned more about immunology, identified new targets and developed novel technologies, fueling optimism about this approach, according to Darrell J. Irvine, an immunology and microbiology researcher at Scripps Research in San Diego, California. “These features, along with new clinical trial designs, are really coming together and making for exciting progress in cancer vaccines,” he said. Twenty-six phase II or III clinical trials testing cancer vaccines are currently in progress, according to Irvine.

During an April 29 session at the American Association for Cancer Research (AACR) Annual Meeting 2025 in Chicago, Irvine led a discussion with other researchers on promising results from two ongoing trials that explore different vaccine approaches. (The AACR publishes Cancer Today.)

Continued Response Following mRNA Vaccination in Pancreatic Cancer

While researchers previously thought vaccines could have little impact on pancreatic cancer outcomes, updated clinical trial data continue to suggest vaccination has the potential to help control the disease.

Vinod P. Balachandran, a surgical oncologist at Memorial Sloan Kettering Cancer Center in New York City, outlined a phase I clinical trial testing an mRNA vaccine in people with pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer. Made popular with early COVID-19 vaccines, mRNA technology can train the body’s immune system to recognize and attack neoantigens, which are proteins only found in cancer cells. In the trial, 16 people with PDAC had the cancer removed with surgery, and investigators used tissue sequencing to identify their cancer’s specific antigens. Researchers then created a personalized vaccine to target those proteins. After receiving immunotherapy, participants received eight weekly doses of the vaccine intravenously, followed by chemotherapy and a booster vaccine dose.

Previously, at the AACR Annual Meeting 2024, Balachandran presented three-year follow-up data from the trial. At that point, half the participants exhibited increased levels of pancreatic cancer-specific T cells. Additionally, people who displayed an immune response had significantly longer recurrence-free survival than those with no response. Of the eight people who responded to the vaccine, six had not had a recurrence.

At this year’s meeting, Balachandran outlined follow-up data at nearly four years, which were also published Feb. 19, 2025, in Nature. Among the eight people who exhibited an initial immune response, six maintained T cells with the ability to target and kill cancer cells at a median of 3.6 years after vaccination.

Researchers also predict the immune cells produced after vaccination have a longer lifespan than previously thought. Investigators used blood analysis to estimate the T cells’ half-life, or the time it takes for half the cells to die. Based on that analysis, researchers found the immune cells have a one-year lifespan after initial vaccination. The booster dose, however, dramatically extends the lifespan. While data presented last year indicated the booster dose extended the immune cells’ lifespan to six years, investigators now project them to live 7.7 years on average. “The vaccine-induced T-cell response appears to have exquisite longevity,” Balachandran said.

With this trial’s results in people with pancreatic cancer, Balachandran suggested this vaccine approach could be translated to other cancer types. “Perhaps this now provides a blueprint to test this more broadly,” he said.

A phase II clinical trial testing the mRNA vaccine in people with PDAC is ongoing.

Off-the-shelf Peptide Vaccines Tested in KRAS-mutated Cancers

Since mRNA vaccines are personalized to each patient, it can take a long time to manufacture each dose. Peptide vaccines, on the other hand, are not personalized and are available off the shelf.

Peptide vaccines consist of peptides, or sequences of molecules that join to form proteins, that induce the immune system to respond to cancer cells. While these vaccines are safe and inexpensive and can be made quickly, so far they have had limited potency in human trials, according to Irvine. But research in the past two decades has allowed investigators to refine their approach to peptide vaccines and has yielded promising results in early-phase clinical trials.

While peptide vaccines can be effective if the molecules reach the lymphatic system—the part of the immune system that carries fluid throughout the body—mice studies found barely any peptide made its way to the lymph nodes. “The vaccine’s actually just not getting to where we need it to go,” Irvine said. Additional research found the vaccine’s small molecules were being pulled into the bloodstream, while larger proteins are too big to go into the blood and would be absorbed into the lymphatic system. Researchers realized adding albumin, a large protein, to the peptide would help the vaccine get to the lymph nodes. Colloquially, Irvine said the albumin acts as a “chaperone” to ensure the peptide gets to its intended destination.

A 2018 study found this new formulation worked in mice. When mice received a vaccine without albumin, the peptide would be present the day after injection, but a week later, it had disappeared. When they received an albumin-containing vaccine, the peptide was still present a week after injection. “This, in turn, has a pretty dramatic impact on the magnitude of the T-cell response,” Irvine said.

In a phase I clinical trial, results of which were published Jan. 9, 2024, in Nature Medicine, investigators tested a peptide vaccine designed to target cancers with G12D and G12R mutations, changes in the KRAS gene that can lead to uncontrolled cell growth. Twenty people with pancreatic cancer and five with colorectal cancer underwent surgery to remove their tumor, followed by chemotherapy and, in some cases, radiation. They then received six vaccine doses across eight weeks. Three months later, they received four weekly booster doses.

After receiving the initial vaccine doses, 21 people, or 84%, exhibited a T-cell response. Compared with their levels at the start of the trial, participants saw their T-cell levels increase 12.75 times. After a median follow-up of 19 months, the median overall survival was 28.9 months, according to updated results presented in December 2024 at the European Society for Medical Oncology Immuno-Oncology Congress in Geneva, Switzerland.

A phase I/II clinical trial is underway to compare the peptide vaccine and standard care in people with KRAS-mutated colorectal and pancreatic cancer, as well as evaluating two different vaccine doses. Initial results are expected later in 2025, Irvine said.

Irvine said there are pros and cons to both mRNA and peptide vaccines. While peptide vaccines can be manufactured much quicker, mRNA vaccines have the potential to be more effective since they are personalized to the individual’s tumor. Oncologists could get the best of both worlds by offering a peptide vaccine immediately to help control disease while a personalized mRNA vaccine is produced, according to Irvine. “There’s actually room to imagine using these in tandem,” he said.

Thomas Celona is an editor at Cancer Today.