Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest five-year survival rates of any cancer, in large part because it is rarely caught early. Most cases are diagnosed at advanced stages, when surgery is no longer an option and systemic treatment options remain limited. For the roughly 10 percent of cases driven by hereditary predisposition, high-risk individuals are currently managed through surveillance — watching and waiting for signs of transformation into cancer with few tools to intervene before that happens.
A Phase 1 clinical trial published July 16 in Cancer Discovery from researchers at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins has now offered the first human evidence that a different approach may be possible. The study tested mKRAS-VAX, an off-the-shelf synthetic long peptide vaccine targeting the six most common KRAS mutations in PDAC, in 20 individuals at high risk of pancreatic cancer due to hereditary predisposition and the presence of a pancreatic lesion on imaging. The vaccine was safe, well tolerated, and stimulated mutant-KRAS-specific T cell responses in 90 percent of participants, responses that remained detectable in the blood for up to two years after vaccination.
"This is an important finding because of the immediate translational opportunity," said Neeha Zaidi, associate professor of oncology at Johns Hopkins and senior author of the study, in a press release. "Overall, this study represents the first proof of concept for the use of vaccines for interception of pancreatic cancer in human patients."
Why KRAS is the target
KRAS mutations are the dominant oncogenic driver in more than 90 percent of PDACs, making them a logical target for a prevention strategy. The same mutations appear in most pancreatic precancer lesions — including the pancreatic intraepithelial neoplasia and intrapapillary mucinous neoplasms that precede invasive disease — creating a window in which an immune intervention could theoretically halt progression before cancer takes hold.
The mKRAS-VAX vaccine targets the six most common KRAS mutations in a single off-the-shelf formulation, meaning it does not need to be individualized for each patient's specific mutation profile. Participants received the vaccine via subcutaneous injection according to a prime-boost schedule — priming doses at weeks one, three, and five, followed by a boost at week 13 — with blood collected at multiple time points and optional annual follow-up visits for long-term immune monitoring.
The Hopkins team previously tested mKRAS-VAX as a post-surgical adjuvant therapy combined with dual immune checkpoint blockade in patients with resected PDAC, with results published in Nature Communications that established safety and early evidence of immune activity in the treatment setting. The new trial is the first to test the vaccine in a prevention context, in people who have not yet developed cancer.
What the trial found
Participants experienced a median 18.2-fold increase in mutant KRAS-specific T cell responses, indicating that the vaccine successfully activated immune cells capable of recognizing KRAS mutations. Those responses included both effector and central memory T cell populations — a distinction that matters for cancer interception, since central memory T cells are longer-lived and better positioned to provide sustained immune surveillance.
"This long-lasting response is particularly noteworthy when assessing for possible interception of cancer, which requires long-lasting immunity," Zaidi said. "In addition, the vaccine was safe and well tolerated, supporting its use in larger cancer interception studies."
After a median follow-up of 16.5 months, none of the vaccinated individuals developed cancer. The researchers also evaluated changes in cyst size as an exploratory endpoint and found a higher rate of cyst reduction or resolution among vaccinated individuals — 37.5 percent — compared with 6.8 percent in an unvaccinated cohort with similar characteristics. The trial was not designed to assess clinical efficacy, and the authors are careful to note that larger studies are needed to establish whether the observed cyst changes were attributable to the vaccine.
"We observed evidence of stability or regression of the pancreatic cysts in association with the induction and durability of KRAS-specific T cell responses," said Michael Goggins, senior author of the study and professor of pathology, medicine, and oncology at Johns Hopkins, in the press release. "However, larger studies are needed to demonstrate that this effect was in fact due to the vaccine."
Where this fits in the KRAS vaccine field
The Hopkins trial adds to a growing body of clinical evidence that KRAS-targeted vaccines can generate meaningful immune responses across different patient populations and formulation strategies. A Phase 1 trial of ELI-002, a lymph node-targeting amphiphile KRAS peptide vaccine, published in Nature Medicine in 2025, reported that patients who completed standard locoregional treatment for minimal residual KRAS-mutant pancreatic or colorectal cancer showed mKRAS-specific T cell responses that correlated with freedom from relapse and death at a median follow-up of nearly 20 months.
The mechanistic premise across these programs is similar — that KRAS mutations, present in the tumor from its earliest stages and detectable in precancerous tissue, represent a stable and broadly shared antigen that can be exploited for immune targeting. The difference between the therapeutic and interception contexts is the patient population: where adjuvant trials enroll people who have already had surgery for confirmed cancer, the Hopkins prevention trial targets individuals who are at high risk but have not yet developed invasive disease.
"Prevention and interception save lives and reduce the morbidity associated with cancer development and progression," said Elizabeth Jaffee, Deputy Director of the Sidney Kimmel Comprehensive Cancer Center and senior author of the study, in the press release. "This is especially important for cancers whose early-onset frequency is increasing and for which we do not have effective methods for early detection."
What comes next
The study's limitations are significant and clearly acknowledged by the authors. The trial enrolled only 20 participants and was designed to assess safety and immunogenicity, not clinical efficacy. The immune analysis was confined to peripheral blood, leaving open the question of whether vaccine-induced T cells are capable of reaching and infiltrating precancerous tissue.
A currently enrolling follow-up trial is designed to address that question directly, assessing changes in precancer tissue alongside blood-based immune monitoring. Zaidi noted in the press release that identifying whether vaccine-induced T cells can infiltrate the precancer lesions — rather than simply circulating in the blood — will be a critical next step in determining whether the vaccine can achieve the kind of local immune engagement that cancer interception would require.
"More studies are needed to find the best vaccine approaches, the best targets, and the ideal timing for vaccination," Jaffee said.
