{
  "abstract": "Background Immune checkpoint inhibitors (ICIs) are ineffective in the ~95% of metastatic colorectal cancers (mCRC) that are mismatch repair proficient or microsatellite stable (MMRp/MSS). Oncogenic KRAS mutations (mKRAS), the most common clonal drivers in MMRp/MSS CRC, are promising targets for cancer vaccines to increase tumor responsiveness to ICIs.Methods We developed mKRAS-VAX, a pooled synthetic long-peptide vaccine covering six KRAS mutations (G12V, G12A, G12R, G12C, G12D, G13D) that collectively occur in over 80% of CRC. We conducted a Phase 1 ( NCT04117087) study of mKRAS-VAX with nivolumab and ipilimumab in patients with MMRp/MSS mCRC refractory to fluoropyrimidines, irinotecan, and oxaliplatin. Priming phase: weekly mKRAS-VAX for 4 weeks, ipilimumab 1mg/kg at weeks 1 and 7, nivolumab 3mg/kg at weeks 1, 4,7 10. Boost phase: mKRAX-VAX every 8 weeks and nivolumab 480mg every 4 weeks up to 1 year total. Primary endpoints were safety and immunogenicity via IFNγ ELISpot. Secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Peripheral and intratumoral T-cell responses were assessed by intracellular cytokine staining and TCRβ sequencing.Results As of data cut-off (February 27, 2025), 13 patients were treated and 12 patients were evaluable for efficacy. All mKRAS-VAX- or vaccine site-related adverse events were grade 1- 2. 9/13 patients (69%) had an immune-related adverse event (irAE) with 4/13 patients (31%) having a grade 3 or 4 irAE – two grade 3 adrenal insufficiency, one grade 3 arthralgia, one grade 4 hyperglycemia. 3/13 patients (23%) discontinued ICIs due to irAEs. mKRAS-VAX induced ex vivo tumor-specific mKRAS T-cell responses in 8/12 (75%; median 8.9-fold increase). 2/12 (17%) patients achieved a RECIST v1.1 partial response, including one with active liver metastases, a disease state increasingly recognized as refractory to immunotherapy. The disease control rate (DCR) was 42% (5/12) with a median PFS of 2.1 months and median OS of 24.9 months. mKRAS-induced T-cells were polyfunctional and infiltrated tumors, comprising up to 9.3% of the intratumoral T-cell repertoire in a patient with an objective response.Conclusions mKRAS-VAX combined with ipilimumab and nivolumab was well-tolerated and resulted in clinical responses in chemorefractory metastatic MMRp/MSS CRC with OS that was provocative. Intratumoral clonal expansion of mKRAS-VAX-induced T-cells in regressing tumors supports the potential of mKRAS-VAX to immunologically target oncogenic KRAS mutations. A Phase 1b trial ( NCT06411691) combining mKRAS-VAX with ICIs balstilimab and botensilimab in advanced MMRp/MSS CRC and pancreatic ductal adenocarcinoma is underway.Trial Registration The study was registered at ClinicalTrials.gov ( NCT04117087).Ethics Approval The study protocol and all amendments were approved by the institutional review board at Johns Hopkins University (IRB00210915). The study was conducted in accordance with the Declaration of Helsinki and good clinical practice guidelines. All participants provided written informed consent.",
  "authors": [
    {
      "affiliations": [
        "Johns Hopkins University, Laurel, MD, USA"
      ],
      "name": "Hejia H Wang"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Amanda L Huff"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Saurav D Haldar"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Maureen Berg"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Christopher Thoburn"
    },
    {
      "affiliations": [
        "Vanderbilt University Medical Center, Nashville, TN, USA"
      ],
      "name": "Thatcher Heumann"
    },
    {
      "affiliations": [
        "Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Robert Anders"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Benjamin Barrett"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Katherine Bever"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Michael Pishvaian"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Valerie Lee"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Dung Le"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Eric Christenson"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Marina Baretti"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Mark Yarchoan"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Daniel Laheru"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Amy Thomas"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Jennifer Durham"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Julie Nauroth"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Jiayu Lu"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Hao Wang"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Elizabeth M Jaffee"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Nilofer S Azad"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Neeha Zaidi"
    }
  ],
  "title": "497 A mutant KRAS peptide vaccine (mKRAS-VAX) combined with immune checkpoint blockade recruits vaccine-induced T-cells into metastatic MMRp/MSS colorectal tumors",
  "uid": "f889865e-610b-50ab-b311-aa7b26657efe"
}