Pancreatic cancer It is among the deadliest types of cancer, but a new experimental therapeutic vaccine shows promise for people with the most common form of the disease.
In January, researchers published results from a Phase 1 trial involving 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 response to fight disease.
The trial included 25 people with pancreatic or colorectal cancer who had previously had surgery, seven of whom had also received radiation therapy. They were administered 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 everyone who received higher doses had a response. Results from the trial, which was funded by Boston-based biotechnology 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 combat common but deadly cancers. Vinod Balachandran of Memorial Sloan Kettering Cancer Center (MSK) and his colleagues used mRNA technology, like that used in COVID vaccines, to combat pancreatic cancer. He results of its phase 1 trial were published in May 2023. And last December, companies Moderna and Merck announced positive results from their latest study of an mRNA vaccine used in combination with the immunotherapy drug Keytruda to treat melanoma.
A challenging form of cancer
He American Cancer Society (ACS) estimates that more than 66,000 people in the US will be diagnosed with pancreatic cancer in 2024, and more than 51,000 people will die from it. The disease represents approximately 3 percent of all cancers and about 7 percent of all cancer deaths. The ACS estimates that about 153,000 people in the country will be diagnosed with colon and rectal cancer this year and that 53,000 people will die from them.
“To a large extent, pancreatic cancer is a very challenging malignancy, and even in the best of circumstances, when you can operate, there is a very high risk of the disease coming back,” he says. Eileen M. O’ReillyMSK gastrointestinal oncologist, lead author of the ELI-002 study.
Some pancreatic cancers and colorectal cancers do not respond to traditional treatments. immunotherapy approaches, such as checkpoint inhibitors. That’s why scientists have begun researching vaccines as a way to prime the immune system more effectively.
“The Elicio trial and the MSK trial analyzing personalized neoantigen vaccines tell us the same thing in a different way: that a very powerful and very specific immune response can be generated in pancreatic and colorectal cancer 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 malignant tumors may indicate a paradigm shift in the way doctors approach and treat these diseases in the future. “We hope this will lead to immunotherapy becoming part of standard treatments in early-stage pancreatic 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 about a third of all cancers. They are found in approximately 95 percent of pancreatic cancers. and 30 to 40 percent of colon cancers. And since the discovery of KRAS mutations in 1983, cancers that had it were thought to be intractable.
“Think about KRAS mutation like a shiny ball. “You can’t hit anything,” he says. SHUBHAM PANTSprofessor of gastrointestinal medical oncology at the University of Texas MD Anderson Cancer Center and senior author of the ELI-002 study.
Drugs targeting cancers with KRAS the mutations must be attached to a protein, Pant says. This is where the cutting-edge management system comes into play. ELI-002 uses technology licensed by the Massachusetts Institute of Technology and developed by Elicio Therapeutics that allows the vaccine to reach the lymph nodes directly.
Peter DeMuthscientific director of Elicio Therapeutics, was part of the team that developed the technology, which was led by David Irvine, professor at MIT and associate director of the Koch Institute for Integrative Cancer Research. One of the questions the MIT team focused on had to do with where vaccines and immunotherapies end up in the body. DeMuth explains that when small vaccine molecules (such as peptides, short strands of DNA, and some proteins) are injected, they are captured by the blood and expelled throughout the body. Some of the vaccine may end up in irrelevant sites where there are no immune cells; some may be degraded or destroyed; and some may flow to places that suppress the immune response or cause toxicity.
In contrast, larger vaccine molecules are too large to enter the bloodstream and can therefore travel directly to the lymphatic system, which is the command center of the body’s immune response.
“So we were designing these molecules with the right activity, but we weren’t paying enough attention to them to get them into the cells where they would have the right action,” DeMuth says.
To close the gap, the team modified the small components of the vaccine to include a fatty acid, allowing the vaccine to adapt effectively. albumin, a common protein found throughout the body. Albumin acts like a molecular 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 bus, where it drives those agents directly to the lymphatic vessels and precisely to the lymph nodes,” DeMuth says.
On January 12, Elicio announced that it had dosed the first participant in its randomized program. ELI-002 phase 2 trial, which will enroll 135 people. The new vaccine targets the seven most common KRAS mutations, which are found in most pancreatic cancers.
Other teams are exploring alternative ways to develop vaccines for pancreatic cancer.
Customized mRNA vaccines
Another new technology being used in the development of new cancer vaccines is Messenger RNA (mRNA). That’s the approach being used in the MSK trial of a personalized mRNA neoantigen vaccine.
Benjamin Greenbaum, co-author of that study’s paper and 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 of KRASmost mutations are specific to an individual’s cancer.
In their trial, the MSK team removed and sequenced participants’ tumors. Then a team from a German biotech company BioNTech (who helped develop one of the COVID vaccines) designed a personalized cancer vaccine that targeted 10 to 20 mutations in each tumor.
“This is where the mRNA made the difference,” Greenbaum says, talking 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 high risk of 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 recently been diagnosed with pancreatic cancer and have not undergone surgery or other treatment. Researchers hope to enroll a total of about 260 people at MSK and nearly 80 other sites globally in the randomized trial.
Greenbaum emphasizes that we are still in the early days, however. “We’re excited to see some promising initial results,” he says. “Whether a personalized strategy is better than a (one-size-fits-all) strategy, what platform is optimal, and how quickly and reliably a personalized vaccine can be manufactured, I think all of those questions will start to be answered once you get started. “Seeing more promising results like this that suggest this is a possible way forward.”