Vaccine Targeting KRAS in Pancreatic and Colorectal Cancer Shows Promise

MSK medical oncologist and pancreatic cancer specialist Eileen O’Reilly.

Medical oncologist Dr. Eileen O’Reilly helped lead a clinical trial investigating a ready-made vaccine as a treatment for pancreatic and colorectal cancers with certain KRAS mutations.

A new vaccine shows encouraging early results as a potential off-the-shelf treatment for certain patients with pancreatic or colorectal cancer, according to a study co-led by researchers at Memorial Sloan Kettering Cancer Center (MSK). The vaccine targets tumors with mutations (or changes) in the KRAS gene, a driving force in many cancers.

This cancer vaccine is different from another type of pancreatic cancer vaccine, which is custom-made for each patient using messenger RNA (mRNA). Both are therapeutic vaccines given after surgery to prevent or delay the cancer from coming back in high-risk patients.

“Having a vaccine that’s ‘off-the-shelf’ would make it easier, faster, and less expensive to treat a larger number of patients,” says medical oncologist and pancreatic cancer specialist Eileen O’Reilly, MD, who helped lead the trial and is one of the corresponding authors in the study published in Nature Medicine. “This gives hope for people with pancreatic and colorectal cancer who have been out of effective treatments when their disease returns.”

Dr. O’Reilly is co-corresponding author of the Nature Medicine study, along with Shubham Pant, MD, of MD Anderson Cancer Center, and Christopher M. Haqq, MD, PhD, of Elicio Therapeutics.

Clinical Trial Results for Pancreatic and Colorectal Cancer KRAS Vaccine

The phase 1 trial involved 25 patients whose pancreatic or colorectal cancer had certain KRAS mutations and were at high risk of the cancer returning after surgery. The results demonstrated this vaccine is safe and appears to stimulate the patient’s immune system to create cancer-fighting cells:

  • 84% of patients had the desired immune response, meaning that immune T cells targeting KRAS-mutated cancer cells were activated and grew in number.
  • Also in 84% of patients, a marker for lingering cancer cells — the amount of tumor DNA circulating in the blood — was reduced. In 24% of patients, the tumor DNA was completely absent.
  • Perhaps most significant, patients who had a higher T cell response also experienced a longer time without the disease returning, known as relapse-free survival.

“In patients whose immune system appeared to respond to the vaccine, the recurrence of cancer was delayed compared with patients who did not respond to the vaccine,” Dr. O’Reilly says. “That’s the type of early clinical effect we can build on.”

How Off-the-Shelf Vaccines Targeting KRAS Mutations Differ From Personalized mRNA Vaccines

A different approach to activating immune cells has been led by surgical oncologist Vinod Balachandran, MD. He is investigating whether a personalized mRNA vaccine using proteins from a patient’s pancreatic tumors will alert their immune system that the cancer cells are foreign. In this way, the mRNA vaccine trains the body to protect itself against cancer cells. This vaccine is now being tested in a phase 2 research study at MSK and other institutions.

Having a vaccine that's 'off-the-shelf' would make it easier, faster, and less expensive to treat a larger number of patients.
Eileen M. O'Reilly medical oncologist

Personalized vaccines — while promising — also have challenges. They take time to make and are costly. By contrast, an off-the-shelf vaccine manufactured in batches could be given to patients with minimal delay and would be cheaper to produce.

“These findings are exciting because they show we may have more than one way to activate immune cells to target pancreatic cancer,” Dr. O’Reilly says.

Targeting KRAS-G12D and KRAS-G12R Mutations

Researchers have long considered KRAS mutations to be a prime target for therapies. Recently, effective drugs have emerged that block a specific KRAS mutation called KRAS-G12C, which is common in lung cancer.

“This was a major breakthrough after decades of trying to find a good KRAS therapy,” Dr. O’Reilly says. “But KRAS-G12C mutations are present in only 1% of pancreatic cancers.”

The new vaccine is able to activate immune cells that target different KRAS mutations called KRAS-G12D and KRAS-G12R, which drive about 90% of pancreatic cancers and 40% of colon cancers. The vaccine contains synthesized peptides (short chains of amino acids) that can launch immune cells to target cancer cells with these mutations.

How the KRAS Vaccine Is Given

The KRAS vaccine is given with a shot in four places — one in each arm and leg. The peptides travel to nearby lymph nodes, which are loaded with the cells critical to generating an effective immune response.

Patients in the trial received the vaccine in two phases — six doses in a primary phase, followed a booster phase with four doses a few months later. The vaccine caused mild side effects such as soreness and fatigue, but Dr. O’Reilly reported it was tolerated better than standard treatments such as chemotherapy, radiation, or targeted drugs.

Positive Early Results Lead to Phase 2 Trial

To confirm these early results, a randomized phase 2 trial opened in December 2023, involving approximately 135 people at multiple U.S. sites who have completed treatment for pancreatic cancer, have tumors with KRAS mutations, and are at high risk for the disease returning. The vaccine for this phase targets more KRAS mutations compared with the initial vaccine. The participants will be split into two groups: two-thirds randomized to receive the vaccine, and one-third to be observed.

“We hope this next phase will give us further proof that vaccines can generate a potent immune response and translate that immune response into improvement in clinical outcomes, especially against pancreatic cancer,” Dr. O’Reilly says. “Many groups at MSK are collaborating on these vaccines and KRAS therapies for pancreatic cancer — and everyone is very interested in learning which are the best approaches to develop. It’s encouraging to know that we could have multiple emerging treatment options for such a difficult disease.”

This trial was sponsored and funded by Elicio Therapeutics. A full list of authors and their disclosures can be found here.