First-in-human testing of a mutant KRAS vaccine for pancreatic cancer interception in high-risk cohorts
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 six 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 1-2. Vaccination elicited a significant mKRAS-specific T cell response in 18/20 participants (90%). Longitudinal TCR 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.
Authors
- Matthew Guo (ORCID: https://orcid.org/0000-0003-4741-7463)
- Neeha Zaidi (ORCID: https://orcid.org/0000-0002-0094-0049)
- Amanda L. Huff (ORCID: https://orcid.org/0000-0002-8423-8985)
- Marina Baretti (ORCID: https://orcid.org/0000-0003-0125-2405)
- Hejia Wang (ORCID: https://orcid.org/0000-0003-1836-7567)
- Christopher J. Thoburn (ORCID: https://orcid.org/0000-0001-7743-9183)
- Daniel A. Laheru (ORCID: https://orcid.org/0000-0001-6646-0200)
- Hassan Sinan (ORCID: https://orcid.org/0009-0000-4402-3499)
- Nancy Sun (ORCID: https://orcid.org/0000-0002-5283-8556)
- Elizabeth Abou Diwan (ORCID: https://orcid.org/0009-0007-4264-9982)
- Won Jin Ho (ORCID: https://orcid.org/0000-0003-2644-5086)
- Elizabeth M. Jaffee (ORCID: https://orcid.org/0000-0003-3841-6549)
- Dimitrios N. Sidiropoulos (ORCID: https://orcid.org/0000-0001-5716-3917)
- Saurav D. Haldar (ORCID: https://orcid.org/0000-0002-2346-0566)
- Jiayun Lu (ORCID: https://orcid.org/0000-0002-5592-6658)
- Nilofer S. Azad (ORCID: https://orcid.org/0000-0002-9613-3988)
- Maureen Berg
- Linda Chi Hang Chu (ORCID: https://orcid.org/0000-0001-9729-2756)
- Mark Yarchoan (ORCID: https://orcid.org/0000-0003-4401-0748)
- Luciane T. Kagohara (ORCID: https://orcid.org/0000-0003-1706-0950)
- Katherine M. Bever (ORCID: https://orcid.org/0000-0001-5230-4661)
- Michael Goggins (ORCID: https://orcid.org/0000-0002-4286-2296)
- Hao Wang (ORCID: https://orcid.org/0000-0001-6489-6940)
- Takeichi Yoshida (ORCID: https://orcid.org/0000-0003-0717-943X)
- Anna Ferguson (ORCID: https://orcid.org/0000-0003-2739-8445)
- Amy M. Thomas
- Julie M. Nauroth
- Zirui Zhu (ORCID: https://orcid.org/0009-0000-8849-1585)
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- Johns Hopkins University (US)
- Johns Hopkins Medicine (US)
- Johns Hopkins Bayview Medical Center (US)
- Johns Hopkins University Applied Physics Laboratory (US)
- Johns Hopkins Hospital (US)
- Sidney Kimmel Comprehensive Cancer Center (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2026-07-16
- DOI
- https://doi.org/10.1158/2159-8290.cd-25-2245
- Primary Topic
- Pancreatic and Hepatic Oncology Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00