Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic cancer, known for being an aggressive tumor often diagnosed in advanced stages. Some individuals are at high risk of developing it due to a hereditary predisposition, making a cancer vaccine crucial. "10% of cases are due to pathogenic mutations in specific cancer susceptibility genes," which can be inherited or arise in response to organ injuries like pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms.
This type of tumor has been increasing in recent years. Mortality has risen in both sexes over the last decade: "8,140 deaths compared to 6,278 in 2014," with an increase in incidence to 9,986 cases in 2024 from 6,367 a decade ago. The projections show a rising incidence, making it the third deadliest cancer in the country, expected to climb a position by 2030.
A new phase 1 clinical trial has tested a vaccine targeting various mutations in the KRAS gene, responsible for over 90% of these tumors, in high-risk patients. The vaccine has proven to be safe, stimulating specific immune responses detectable in blood up to two years later in 90% of study participants. The study is published in Cancer Discovery.
"Individuals at high risk due to hereditary predisposition or the presence of concerning pancreatic lesions detected in imaging tests often undergo monitoring to track changes over time," explains Neeha Zaidi, associate professor of oncology at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center and one of the study's leaders.
Pancreatic Cancer: The Silent Tumor Growing Due to Risk Factors like Obesity and Smoking
"If there is a high enough concern for cancer transformation or if early-stage cancer is detected, the current standard treatment is surgical resection," says Zaidi. However, she adds, "recurrence rates can reach up to 80%, and many precursor lesions of pancreatic cancer are microscopic and therefore undetectable by imaging techniques."
The research team reasoned that intercepting cancer development through non-invasive approaches could be an effective strategy to prevent PDAC and improve survival in high-risk individuals.
"Prevention and interception save lives and reduce the morbidity associated with cancer development and progression. This is especially crucial for cancers with increasing early occurrence rates and lacking effective early detection methods," states another lead author, Elizabeth Jaffee, deputy director of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center.
"A successful intervention that could reduce pancreatic cancer incidence would be a significant achievement," added the third author, Michael G. Goggins, professor of pathology, medicine, and oncology, and holder of the Sol Goldman Chair in Pancreatic Cancer Research at the Johns Hopkins University School of Medicine.
How Does mKRAS-VAX, the Pancreatic Cancer Vaccine, Work?
Mutations in the KRAS gene are the main oncogenic factors in over 90% of pancreatic ductal adenocarcinomas. Researchers had previously developed mKRAS-VAX, a synthetic long-peptide vaccine ready for use targeting the six most common KRAS gene mutations found in PDAC and most pancreatic precancerous lesions.
In the new study, the team conducted a phase I clinical trial to evaluate mKRAS-VAX vaccination in 20 high-risk individuals with a hereditary predisposition and radiographic evidence of a pancreatic lesion, typically in the form of a small cyst.
"The goal of this study was to evaluate the vaccine's safety and induction of lasting immune responses," says Jaffee. She added that the trial was based on preclinical data showing the ability of a KRAS gene-targeted vaccine to prevent early precancerous lesion progression in a genetically modified murine model of KRAS-driven pancreatic cancer.
Study participants received mKRAS-VAX via subcutaneous injections following a priming-boost vaccination strategy, with doses at weeks 1, 3, and 5 and a booster dose at week 9. This scheme aims to teach the immune system to recognize a pathogen, followed by one or more booster doses. Blood samples were taken at different times, and optional annual follow-up visits were offered for long-term immunological monitoring.
What Are the Expert Evaluations?
Given that this is a very early-phase trial, experts are cautious. Some voices, as reported by the Science Media Centre in Spain, point out that "it is about defining safety and surrogate evidence of function (induced responses)." Manel Juan, head of the Immunology Service at Hospital Clínic, adds that "efficacy still needs to be demonstrated, possibly only achievable by combining vaccination with other immunotherapies based on this safety."
According to Ignacio Melero, professor of Immunology at the University of Navarra and researcher at CIMA, "it is an interesting study on immunogenicity, but it is too early to know if it will actually intercept pancreatic cancer cases in genetically predisposed families." Currently, the sample only covers the experience with 20 subjects, and "efficacy is not demonstrated," Melero adds.
Manel Juan emphasizes that "preventive use would be conceptually possible outside of familial cases but hardly applicable in most cases (which are sporadic)."