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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月23日

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  • Hejia Henry Wang,
  • Amanda L. Huff,
  • S. Daniel Haldar,
  • Maureen Berg,
  • Christopher Thoburn,
  • Thatcher R. Heumann,
  • Robert A. Anders,
  • Benjamin Barrett,
  • Katherine M. Bever,
  • Michael J. Pishvaian,
  • Valerie Lee,
  • Dung T. Le,
  • Eric S. Christenson,
  • Marina Baretti,
  • Mark Yarchoan,
  • Daniel Laheru,
  • Amy Thomas,
  • Jennifer N. Durham,
  • Julie M. Nauroth,
  • Jiayun Lu,
  • Hao Wang,
  • Elizabeth M. Jaffee,
  • Nilofer S. Azad,
  • Neeha Zaidi

摘要

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.