First-in-human testing of a mutant KRAS vaccine for pancreatic cancer interception in high-risk cohorts
(1) Haldar SD (2) Huff AL (3) Wang HH (4) Zhu Z (5) Berg M (6) Lu J (7) Sun N (8) Abou Diwan E (9) Sinan H (10) Thoburn CJ (11) Guo MZ (12) Yoshida T (13) Chu LC (14) Ferguson AK (15) Sidiropoulos DN (16) Kagohara LT (17) Ho WJ (18) Bever KM (19) Baretti M (20) Yarchoan M (21) Laheru DA (22) Nauroth JM (23) Thomas AM (24) Wang H (25) Azad NS (26) Goggins MG (27) Jaffee EM (28) Zaidi N
In a phase 1 trial, Haldar, Huff, et al. treated 20 volunteers with high-risk of PDAC development (based on family history or genetics, plus radiographic indication of a precursor lesion/cyst) with a prophylactic SLP vaccine against 6 common KRAS mutations. The vaccine was well tolerated, and 90% of recipients developed mutant KRAS-specific T cell responses, although response rates varied against individual KRAS mutations. Polyfunctional, memory mKRAS-specific CD4+ and CD8+ T cells and novel clonotypes were detected and persisted 1-2 years after vaccination. No patients developed PDAC over a 16.5-month follow-up, and many had evidence of cyst regression or resolution.
Contributed by Alex Najibi
(1) Haldar SD (2) Huff AL (3) Wang HH (4) Zhu Z (5) Berg M (6) Lu J (7) Sun N (8) Abou Diwan E (9) Sinan H (10) Thoburn CJ (11) Guo MZ (12) Yoshida T (13) Chu LC (14) Ferguson AK (15) Sidiropoulos DN (16) Kagohara LT (17) Ho WJ (18) Bever KM (19) Baretti M (20) Yarchoan M (21) Laheru DA (22) Nauroth JM (23) Thomas AM (24) Wang H (25) Azad NS (26) Goggins MG (27) Jaffee EM (28) Zaidi N
In a phase 1 trial, Haldar, Huff, et al. treated 20 volunteers with high-risk of PDAC development (based on family history or genetics, plus radiographic indication of a precursor lesion/cyst) with a prophylactic SLP vaccine against 6 common KRAS mutations. The vaccine was well tolerated, and 90% of recipients developed mutant KRAS-specific T cell responses, although response rates varied against individual KRAS mutations. Polyfunctional, memory mKRAS-specific CD4+ and CD8+ T cells and novel clonotypes were detected and persisted 1-2 years after vaccination. No patients developed PDAC over a 16.5-month follow-up, and many had evidence of cyst regression or resolution.
Contributed by Alex Najibi
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 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.
Author Info:
(1) The University of Texas MD Anderson Cancer Center Houston, TX United States. ROR: https://ror.org/04twxam07 (2) Johns Hopkins Medicine Baltimore United States. ROR: https://ror
.org/037zgn354 (3) Johns Hopkins Medicine Baltimore, Maryland United States. ROR: https://ror.org/037zgn354 (4) Johns Hopkins Medicine Baltimore, Maryland United States. ROR: https://ror.org/037zgn354 (5) Johns Hopkins Medicine Baltimore, MD United States. ROR: https://ror.org/037zgn354 (6) Johns Hopkins University United States. ROR: https://ror.org/00za53h95 (7) Johns Hopkins Medicine Baltimore, MD United States. ROR: https://ror.org/037zgn354 (8) Johns Hopkins School of Medicine Baltimore, MD United States. (9) Icahn School of Medicine at Mount Sinai New York United States. ROR: https://ror.org/04a9tmd77 (10) Johns Hopkins Medicine Baltimore, MD United States. ROR: https://ror.org/037zgn354 (11) Johns Hopkins Medicine Baltimore United States. ROR: https://ror.org/037zgn354 (12) The Johns Hopkins Medical Institutions Baltimore, MD United States. (13) Johns Hopkins University Baltimore, MD United States. ROR: https://ror.org/00za53h95 (14) Johns Hopkins University Baltimore, MD United States. ROR: https://ror.org/00za53h95 (15) Johns Hopkins Medicine Baltimore United States. ROR: https://ror.org/037zgn354 (16) Johns Hopkins University Baltimore, MD United States. ROR: https://ror.org/00za53h95 (17) Johns Hopkins University Baltimore, MD United States. ROR: https://ror.org/00za53h95 (18) Sidney Kimmel Comprehensive Cancer Center Baltimore, Maryland United States. ROR: https://ror.org/05m5b8x20 (19) Johns Hopkins Medicine Baltimore, MD United States. ROR: https://ror.org/037zgn354 (20) Johns Hopkins Medicine Baltimore, MD United States. ROR: https://ror.org/037zgn354 (21) Sidney Kimmel Comprehensive Cancer Center Baltimore, MD United States. ROR: https://ror.org/05m5b8x20 (22) Johns Hopkins University Baltimore, MD United States. ROR: https://ror.org/00za53h95 (23) Johns Hopkins Medicine Baltimore, MD United States. ROR: https://ror.org/037zgn354 (24) Johns Hopkins Medicine Baltimore United States. ROR: https://ror.org/037zgn354 (25) Johns Hopkins University Baltimore, Maryland United States. ROR: https://ror.org/00za53h95 (26) Johns Hopkins University Baltimore, MD United States. ROR: https://ror.org/00za53h95 (27) Johns Hopkins University Baltimore, MD United States. ROR: https://ror.org/00za53h95 (28) Johns Hopkins Medicine Baltimore, Maryland United States. ROR: https://ror.org/037zgn354
Citation: Cancer Discov 2026 Jul 16 Epub07/16/2026
