A Pancreatic Cancer Vaccine Shows Promise in a Phase 1 Clinical Trial

Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is often not detected until the advanced stages because of the limited symptoms it causes early on, leading to poor survival rates for patients. However, PDAC tumors develop slowly over decades from more benign cysts or lesions. Since 10 percent of people who develop PDAC have a genetic predisposition, this provides an opportunity for clinicians to introduce interventions early that could delay or even completely prevent the progression of pancreatic cancer.¹

A team of researchers at Johns Hopkins University explored the potential of a vaccine targeting the most common mutations in the KRAS gene, one of the most frequently affected cell growth genes in PDAC and pancreatic lesions, for high-risk individuals.^2,3 In a Phase 1 clinical trial, the team showed that this cancer vaccine induced protective, antigen-specific T cell responses and slowed the progression of lesions to pancreatic cancer in participants with these growths.⁴ The findings, published in Cancer Discovery, show the potential for this therapy and support its exploration in larger trials.

“This is just the beginning, but the findings suggest that the immune system is getting activated,” said Elizabeth Jaffee, an oncologist and study coauthor in a press release.

The researchers identified the six most common mutant KRAS (mKRAS) variations in PDAC tumors and incorporated them into a peptide-based vaccine. Previously, the team showed that the vaccine was safe and elicited mKRAS-specific T cells when administered to people with PDAC while they were receiving monoclonal antibody therapy or had undergone surgery and follow-up cancer treatment.⁵

In the present trial, the researcher team recruited individuals with a genetic predisposition for PDAC and confirmation of pancreatic lesions that have not proceeded to cancer. They administered their peptide-based mKRAS vaccine to the 20 patients who met these criteria in a series of four immunization timepoints, including one booster dose four weeks after the final prime dose. At each visit and four weeks after the final vaccination, the researchers collected peripheral blood mononuclear cells to assess immune responses.

Overall, patients reported only mild side effects, such as fatigue, chills, and flu-like symptoms, that all resolved on their own. Comparing the patients’ T cells responses from before and after vaccination, the researchers observed a median 18.2-fold increase in T cell responses against all mKRAS antigens in the vaccine. Although they saw differences in the immunogenicity, or overall immune response, across the six antigens, half of the patients produced strong responses against all of the peptides.

Looking at a 16.5-month median follow-up, the researchers reported that none of the vaccinated participants had any progression in their noninvasive cysts and lesions to pancreatic tumors. In fact, three patients had their cysts completely resolve while another three individuals’ lesions regressed; all the remaining participants’ lesions remained stable. When the researchers compared this to an unvaccinated cohort monitored over a similar period of time, they saw more progression in this group compared to their vaccinated patients.

In a subset of patients who returned for optional follow-ups one or two years after the last round of vaccination, the researchers saw that the vaccine stimulated both CD4⁺ and CD8⁺ T cells, including effector and central memory phenotypes. Although the team saw these cell populations decline over time, the researchers showed that these cells produced robust responses and expansion potential upon restimulation with mKRAS antigen in ex vivo studies.

“Overall, this study represents the first proof of concept for the use of vaccines for interception of pancreatic cancer in human patients,” oncologist and study coauthor Neeha Zaidi said in the same press release.

Disclosure of Conflict of Interest: Elizabeth Jaffee and Neeha Zaid are founders and consultants for Adventris Pharmaceuticals, of which they both also hold equity in. Some of the technology used in this study was also licensed by Adventris Pharmaceuticals from Johns Hopkins University.