ROCHESTER, Minn. — An investigational vaccine helped the immune system recognize and respond to mutations that drive most pancreatic cancers, according to results from a randomized phase 2 clinical trial led by Mayo Clinic researchers. The findings, published in Nature Medicine, will help researchers design a larger phase 3 clinical trial.
Nearly every patient evaluated after receiving the vaccine developed an immune response against mutated KRAS, a gene that plays a major role in pancreatic cancer . Mayo Clinic researchers also found that patients with stronger immune responses tended to remain free of disease longer.
"Historically, pancreatic cancer has been very difficult to treat with immunotherapy," says Ben George, M.B.B.S, M.D. , a Mayo Clinic medical oncologist and lead author of the study. "What is encouraging is that we were able to generate a strong immune response against KRAS mutations in nearly every patient we evaluated. In an exploratory analysis, patients with greater immune responses to the vaccine appeared protected with longer disease-free survival times."
Teaching the immune system what to attack
Pancreatic cancer has a high risk of returning even after surgery and chemotherapy. Researchers have been looking for new ways to find and destroy cancer cells that may remain in the body after treatment.
KRAS offers one possible target.
Mutations in the KRAS gene are found in about 90% of pancreatic ductal adenocarcinomas , the most common type of pancreatic cancer. These mutations help cancer cells grow and survive.
The investigational vaccine targets seven of the most common KRAS mutations. It is designed to travel to the lymph nodes, where many immune responses begin. There, the vaccine helps T cells — which are immune cells that can recognize and attack altered cells — to identify cancer cells with mutated KRAS.
Unlike some cancer vaccines made specifically for an individual patient, this vaccine is "off the shelf" and designed for patients whose tumors have one of the KRAS mutations it targets.
The study included 144 patients with stage 1-3 KRAS-mutated pancreatic cancer. All had undergone surgery and chemotherapy and had no cancer visible on imaging when they entered the trial.
Researchers randomly assigned 96 patients to receive the vaccine and 48 to observation.
Strong immune response, but more study is needed
The trial did not meet its primary goal of showing an improvement in disease-free survival across the full study population.
Median disease-free survival, or the length of time patients lived without their cancer returning, was 23.8 months for patients who received the vaccine and 21.2 months for those in the observation group. The difference was not statistically significant.
Researchers found other signals that warrant further study.
Of the 90 patients who received the vaccine and could be evaluated for immune response, 89, or 98.9%, developed increased T-cell responses against mutated KRAS.
Researchers also found an association between the strength of the immune response and how long patients remained free of disease. More than 8 in 10 patients who were able to be evaluated developed a KRAS-specific T-cell response that was more than 9 times greater than before vaccination. Patients who reached that level had longer disease-free survival than those who did not.
"The immune response is an important signal that helps us understand what is happening biologically and gives us important information for the next trial," Dr. George says.
Clues about who may benefit
Researchers also found clues that may help predict which patients are more likely to benefit from the vaccine.
One clue involved circulating tumor DNA, or ctDNA. These are small pieces of DNA released by cancer cells into the bloodstream. Detecting ctDNA after cancer treatment can be a sign that cancer remains in the body even when it cannot be seen on imaging.
In a planned analysis, patients who did not have detectable ctDNA at the start of the study showed a signal of longer disease-free survival with the vaccine compared with observation.
Researchers saw another difference based on whether patients had previously received radiation therapy.
Patients who had received radiation had fewer lymphocytes, a type of white blood cell important to the immune system. They also developed weaker KRAS-specific immune responses after receiving the vaccine. Among patients who had not received radiation, researchers saw a signal of longer disease-free survival with the vaccine.
These findings do not establish which patients will benefit from the vaccine. They do, however, give researchers information to test in a larger trial.
"One of the most useful things we can learn from a phase 2 trial is why patients may respond differently," Dr. George says. "We can take those lessons and design the next study to better answer the question that matters most: Can this approach help patients live longer without their pancreatic cancer returning?"
Building an immune response against cancer
Researchers found that the vaccine activated two important types of T cells, known as CD4 and CD8 T cells. It also produced immune responses against several KRAS mutations.
In a small group of patients, researchers observed another potentially important effect. After vaccination, the immune system began recognizing other cancer-related targets that were not included in the vaccine, a phenomenon researchers call antigen spreading.
The immune response also persisted over time. Among patients who could be evaluated at least 46 weeks after the start of the study, 95.5% still had a detectable KRAS-specific T-cell response.
Researchers say longer follow-up and a larger study are needed. Overall survival results are not yet available, and some findings linking immune response with disease-free survival came from exploratory analyses.
A phase 3 clinical trial is planned to further study whether the vaccine can delay or prevent pancreatic cancer from returning.
"We've shown that we can teach the immune system to recognize these KRAS mutations," Dr. George says. "The next step is finding out whether doing that can change the course of the disease for patients."
For a complete list of authors, disclosures and funding, review the publication .
