Mutant KRAS peptide vaccine with dual checkpoint blockade in metastatic colorectal cancer: a phase I trial.

“Mutant KRAS peptide vaccine with dual checkpoint blockade in metastatic colorectal cancer: a phase I trial. Wang HH(1)(2)(3), Huff AL(1)(2)(3), Haldar SD(1)(2)(3)(4), Berg M(1), Thoburn C(1)(2)(3), Heumann TR(1)(2)(3)(5), Anders RA(2)(3)(6), Barrett B(1)(2)(3), Bever KM(1)(2)(3), Pishvaian MJ(1), Lee V(1), Le DT(1)(2)(3), Christenson ES(1)(2)(3), Baretti M(1)(2)(3), Yarchoan M(1)(2)(3), Laheru D(1)(2)(3), Thomas A(1), Durham JN(1)(2)(3), Nauroth JM(1)(2)(3), Lu J(1), Wang H(1), Jaffee EM(1)(2)(3), Azad NS(7)(8)(9), Zaidi N(10)(11)(12). Author information: (1)Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (2)Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (3)The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (4)Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (5)Department of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. (6)Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (7)Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. nilo.azad@jhu.edu. (8)Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. nilo.azad@jhu.edu. (9)The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. nilo.azad@jhu.edu. (10)Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. nzaidi1@jhmi.edu. (11)Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. nzaidi1@jhmi.edu. (12)The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. nzaidi1@jhmi.edu. Immune checkpoint inhibitors (ICIs) have limited activity in mismatch repair proficient or microsatellite stable (MMRp/MSS) colorectal cancer (CRC). KRAS mutations, present in approximately 40% of these cancers, can generate neoantigens that are targets for therapeutic vaccines. In this single-arm, phase I study (NCT04117087), we evaluated mKRAS-VAX, a pooled mutant KRAS (mKRAS) peptide vaccine targeting six KRAS mutations with nivolumab and ipilimumab in 13 patients with pretreated metastatic MMRp/MSS CRC. Both primary endpoints of safety and immunogenicity (within 17 weeks post-vaccination) were met. Secondary endpoints included treatment efficacy defined by RECIST v1.1 criteria. All adverse events attributed to mKRAS-VAX were grade 1 or 2, and the addition of mKRAS-VAX did not increase the frequency of severe immune-related adverse events beyond the expected profile of dual ICIs alone. mKRAS-VAX elicited an increase in tumor-specific mKRAS-reactive T-cells in 8/12 biomarker-evaluable patients (75%) by direct ex vivo IFNγ ELISpot and in 12 patients (100%) following in vitro expansion. Our findings support further development of mKRAS vaccines with ICIs for advanced MMRp/MSS CRC. © 2026. The Author(s). Conflict of interest statement: Competing interests: A.L.H. is a consultant for Adventris Pharmaceuticals. S.D.H. reports research funding from Shionogi, Summit Therapeutics, Bristol Myers Squibb, and travel/honoraria from DAVA Oncology. K.M.B. reports research support from BMS and Merck. Her spouse is an employee of AstraZeneca. D.T.L. is a consultant for Bristol Myers Squibb. E.S.C. reports grant/research support from Affimed GMBH, Parabilis, Haystack, Incyte, NextCure, Pfizer, and Regeneron. E.S.C. is a consultant for Parabilis, Roche, Seres Therapeutics, SirTex, and Urogen. M.Y. receives grant/research support (to Johns Hopkins) from Bristol-Myers Squibb, Exelixis, Incyte, and Genentech; receives honoraria from Exelixis, AstraZeneca, Lantheus, Genentech, and Incyte; M.Y. is the co-inventor of patents related to cancer vaccines (patents managed by Johns Hopkins); and is a cofounder with equity of Adventris Pharmaceuticals. E.M.J. reports other support from Abmeta and Adventris, personal fees from Dragonfly, Neuvogen, Surge Tx, Mestag, HDTbio, and grants from Lustgarten, Genentech, BMS, NeoTx, and Break Through Cancer. E.M.J. is a founder of, holds equity in, and serves as a consultant to Adventris Pharmaceuticals. Furthermore, Adventris Pharmaceuticals has licensed a technology described in this study from the Johns Hopkins University. As a result of that agreement, Dr. Jaffee and the University are entitled to royalty distributions related to technology described in the study discussed in this publication. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. N.S.A. is a paid consultant for Mirati and QED, receives institutional funding from Agios Inc, Array, Atlas, Bayer HealthCare, Bristol Myers Squibb, Celgene, Debio, Eli Lilly and Company, EMD Serono, Incyte Corporation, Intensity, Merck & Co., and Taiho Pharmaceuticals Co. Ltd. Dr. Azad participates on advisory boards for Incyte, QED, and GlaxoSmithKline. N.Z. reports research support from Bristol Myers Squibb, is a consultant for Genentech, and receives other support from Adventris Pharmaceuticals. A.H.L., M.Y., E.M.J., and N.Z. have currently filed patents related to the KRAS peptide vaccine. The other authors declare no competing interests.”