First-in-Human Testing of a Mutant KRAS Vaccine for Pancreatic Cancer Interception in High-risk Cohorts

Abstract Pancreatic ductal adenocarcinoma (PDAC) arises from precursor lesions over a decade-plus, offering a window for interception in high-risk individuals, but current surveillance detects a minority of precursors. Mutant KRAS (mKRAS) is present in most PDACs and their precursors, making it an appealing target for immune-based interception. We conducted a phase I, first-in-human study of a peptide vaccine targeting 6 common KRAS mutations (mKRAS-VAX) in 20 individuals with hereditary PDAC predisposition and a radiographic pancreatic abnormality (NCT05013216) to assess safety, immunogenicity, and T-cell persistence. Adverse events were grade 1 to 2. Vaccination elicited a significant mKRAS-specific T-cell response in 18 of 20 (90%) participants. Longitudinal T-cell receptor sequencing demonstrated persistence of vaccine-induced mKRAS-specific clonotypes for up to 2 years. Over a median follow-up of 16.5 months, no participants developed PDAC. These findings demonstrate that mKRAS-VAX is safe and generates durable T-cell responses, which support the advancement of mKRAS-targeted vaccination for PDAC interception. Significance: In high-risk individuals with hereditary predisposition to PDAC, a first-in-human peptide vaccine targeting mKRAS (mKRAS-VAX) was safe and elicited durable T-cell responses, supporting further development of mKRAS-targeted vaccination for immune interception for pancreatic precancers.