Pancreatic cancer is among the deadliest types of cancer, but a new experimental therapeutic vaccine appears promising for people with the most common form of the disease.
In January researchers published results of a phase 1 trial that involved people with so-called KRAS-mutated pancreatic or colorectal cancer who were at high risk of relapse and showed early signs of tumor resurgence. The new vaccine delivers tumor-targeting molecules directly into the lymph nodes. There, it activates T cells, immune cells that play a critical role in the body’s disease-fighting response.
The trial included 25 people with pancreatic or colorectal cancer who had previously undergone surgery, seven of whom also had received radiation therapy. They were given up to 10 doses of the vaccine known as ELI-002, and the results were promising: 84 percent of all participants had positive T cell responses—and all of those who received higher doses had a response. The results of the trial, which was funded by Boston-based biotech company Elicio Therapeutics, were published in Nature Medicine.
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This is just the latest example of how scientists are using vaccines to battle common but deadly cancers. Vinod Balachandran of Memorial Sloan Kettering Cancer Center (MSK) and his colleagues used mRNA technology—like that used in the COVID vaccines—to fight pancreatic cancer. The results of their phase 1 trial were published in May 2023. And last December the companies Moderna and Merck announced positive results from their latest study of an mRNA vaccine used in combination with the immunotherapy drug Keytruda for treating melanoma.
A Challenging Form of Cancer
The American Cancer Society (ACS) estimates that more than 66,000 people in the U.S. will be diagnosed with pancreatic cancer in 2024, and more than 51,000 people will die of it. The disease accounts for about 3 percent of all cancers and about 7 percent of all cancer deaths. The ACS estimates that nearly 153,000 people in the country will be diagnosed with colon and rectal cancers this year and that 53,000 people will die from them.
“In large part, pancreas cancer is a very challenging malignancy, and even in the best set of circumstances when it’s able to be operated upon, there is a very high risk of the disease recurring," says Eileen M. O’Reilly, a gastrointestinal oncologist at MSK, who was senior author of the ELI-002 study.
Most pancreatic cancers and some colorectal cancers do not respond to traditional immunotherapy approaches, such as checkpoint inhibitors. So scientists have started investigating vaccines as a way to prime the immune system more effectively.
“The Elicio trial and the MSK trial looking at personalized neoantigen vaccines both tell us the same thing in a different way: that a very potent and very specific immune response in pancreas and colorectal cancer can be generated and that the [vaccines are] safe, feasible and [lead] to an early clinical signal,” O’Reilly says. She adds that the observation and interpretation that an immune response can be generated in highly challenging malignancies may indicate a paradigm shift in the way that physicians approach and treat these diseases in the future. “We’re hoping that this will lead to immunotherapy becoming part of standard treatments in early-stage pancreas cancer,” she says.
A Shuttle Bus to the Lymph Nodes
ELI-002 is a peptide-based vaccine that targets two of the most common mutations in the KRAS gene, called G12D and G12R. This is significant because KRAS mutations cause roughly one third of all cancers. They’re found in about 95 percent of pancreatic cancers and 30 to 40 percent of colon cancers. And since the discovery of KRAS mutations in 1983, cancers that have it have been thought to be untreatable.
“Think of the KRAS mutation like a shiny ball. You can’t stick anything to it,” says Shubham Pant, a professor of gastrointestinal medical oncology at the University of Texas MD Anderson Cancer Center and lead author of the ELI-002 study.
Drugs targeting cancers with KRAS mutations must be stuck to a protein, Pant says. This is where the cutting-edge delivery system comes in. ELI-002 uses technology licensed from the Massachusetts Institute of Technology and developed by Elicio Therapeutics that allows the vaccine to hitchhike a ride directly into the lymph nodes.
Peter DeMuth, chief scientific officer at Elicio Therapeutics, was part of the team that developed the technology, which was led by Darrell Irvine, a professor at M.I.T. and an associate director of the Koch Institute for Integrative Cancer Research. One of the issues the M.I.T. team focused on involved the location in the body where vaccines and immunotherapies end up. DeMuth explains that when small vaccine molecules (such as peptides, short strands of DNA and some proteins) are injected, the blood captures them and flushes them through the body. Some of the vaccine may end up at irrelevant sites where there are no immune cells; some may get degraded or destroyed; and some may flow to places that suppress the immune response or lead to toxicity.
In contrast, larger vaccine molecules are too big to enter the bloodstream and can thus travel straight to the lymph system, which is the body’s immune response command center.
“So we were designing these molecules with the right activity, but we weren’t giving enough attention to getting them to the cells where they’re going to have the right action,” DeMuth says.
In order to bridge the gap, the team modified the small vaccine components to include a fatty acid, which enables the vaccine to effectively hitch a ride on albumin, a common protein found throughout the body. Albumin serves as a molecular shuttle bus, with pockets on its surface where fatty acids can bind to it. “By giving the vaccine a fatty acid, it’s like giving it a ticket to ride the albumin shuttle bus, where it drives those agents directly into the lymph vessels and precisely into the lymph nodes,” DeMuth says.
On January 12 Elicio announced that it had dosed the first participant in its randomized phase 2 trial of ELI-002, which will enroll 135 people. The new vaccine targets the seven most common KRAS mutations, which are found in the majority of pancreatic cancers.
Other teams are exploring alternative ways to develop vaccines for pancreatic cancer.
Personalized mRNA Vaccines
Another new technology being used in the development of novel cancer vaccines is messenger RNA (mRNA). That’s the approach being used in the MSK trial of a personalized mRNA neoantigen vaccine.
Benjamin Greenbaum, a co-author of that study’s paper and the director of computational immuno-oncology at MSK, explains that when cancer cells evolve, they create potential targets, or neoantigens, for the immune system to fight. Apart from what Greenbaum calls hotspot mutations, such as those in KRAS, most mutations are specific to an individual’s cancer.
In its trial, the MSK team removed and sequenced participants’ tumors. Then a team at German biotech company BioNTech (which helped develop one of the COVID vaccines) created a personalized cancer vaccine that targeted up to 20 mutations in each tumor.
“This is where mRNA was a difference-maker,” Greenbaum says, speaking about the speed of the process. “[BioNTech was] able to get the vaccine to us in about nine weeks.”
There were 16 people in the trial, all of whom had had their tumors removed but were at a high risk of having a recurrence. Half of the participants had an immune response after receiving the personalized vaccine in combination with an immune checkpoint inhibitor and chemotherapy.
MSK launched a phase 2 trial last October, which is open to people who have been newly diagnosed with pancreatic cancer who haven’t had surgery or other treatment. Researchers expect to enroll a total of about 260 people at MSK and nearly 80 other sites globally in the randomized trial.
Greenbaum emphasizes that these are early days, however. “We’re just excited to see some promising initial results,” he says. “Whether a personalized strategy is better than a [one-size-fits-all] strategy, which platform is optimal and how quickly and reliably a personalized vaccine can be manufactured—I think all of those questions will start to get answered once you start to see more promising results like this that suggest this is a possible pathway forward.”