{
  "abstract": "Background Human Endogenous Retroviruses (HERVs) are remnants of ancient viral infections that have become permanently integrated into the human genome. Among them, HERV-K stands out due to its aberrant reactivation in solid tumors while remaining silent in healthy tissues, positioning it as a compelling cancer antigen. Elevated HERV-K levels have been linked to poor clinical outcomes, underscoring its relevance in tumor progression. Furthermore, HERV-K is upregulated during aging and cellular senescence—two biological processes increasingly implicated in cancer development. These findings highlight HERV-K as a promising target for immunotherapeutic intervention. This study investigates the therapeutic potential of re-engineered strategies to target HERV-K, aiming to exploit its tumor-restricted expression for precision oncology.Methods HERV-K expression was profiled in late-stage cancer patients across >40 cancer types using RNA-seq data. IPT001, a novel adenoviral vector platform to deliver virus-like particles (VLPs) encoding HERV-K proteins with a strategic immunostimulatory point mutation, was developed ( figure 1A). Immunogenicity was assessed in vitro in human PBMCs as well as in vivo in mice and non-human primates. HERV-K-specific T-cell recognition of tumor cells was evaluated in HLA-restricted assays. Therapeutic efficacy was tested in a HERV-K-expressing renal cell carcinoma (RENCA)-based murine tumor model, including a combination arm with anti-PD-1 checkpoint blockade.Results Transcriptomic analysis demonstrated consistent upregulation of HERV-K across multiple solid tumor types, reinforcing its role as a cancer antigen. In ex vivo human PBMC cultures, the therapeutic candidate IPT001 effectively primed and expanded CD8+ and CD4+ T-cells specific for HERV-K. These T-cells exhibited functional activation upon co-culture with HLA-matched HERV-K-expressing cancer cell lines, confirming antigen specificity. In vivo, IPT001 elicited strong HERV-K-specific cellular and humoral immune responses in murine models. In the RENCA tumor model, IPT001 treatment significantly reduced tumor burden. Expanding on previous findings in a murine colorectal cancer model targeting murine ERVs alongside checkpoint blockade, combination of ITP001 with anti-PD-1 therapy yielded synergistic anti-tumor activity in the RENCA model. (figure 1B-1C).Conclusions This study establishes IPT001 as a promising immunotherapeutic targeting HERV-K, a previously undruggable cancer antigen. Through engineered immunostimulatory mutations, IPT001 overcame HERV-K´s intrinsic low immunogenicity, inducing potent cellular and humoral responses. The observed tumor regression and synergy with PD-1 blockade in preclinical models position HERV-K as a compelling cancer antigen with strong clinical translation potential. Future clinical studies are warranted to validate the efficacy of IPT001 as a monotherapy and in combination with standard-of-care treatments, including immune checkpoint inhibitors.Abstract 646 Figure 1",
  "authors": [
    {
      "affiliations": [
        "HERVolution Therapeutics, Frederiksberg, Capital Region of Denmark, Denmark"
      ],
      "name": "Maria Perez Penco"
    },
    {
      "affiliations": [
        "HERVolution Therapeutics, Frederiksberg, Capital Region of Denmark, Denmark",
        "Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Capital Region of Denmark, Denmark"
      ],
      "name": "Lasse Neukirch"
    },
    {
      "affiliations": [
        "HERVolution Therapeutics, Frederiksberg, Capital Region of Denmark, Denmark",
        "Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Capital Region of Denmark, Denmark"
      ],
      "name": "Emeline Ragonnaud"
    },
    {
      "affiliations": [
        "HERVolution Therapeutics, Frederiksberg, Capital Region of Denmark, Denmark",
        "Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Capital Region of Denmark, Denmark"
      ],
      "name": "Mikkel Dons Müller"
    },
    {
      "affiliations": [
        "Center for Genomic Medicine, Rigshospitalet, Copenhagen, Capital Region of Denmark, Denmark"
      ],
      "name": "Frederik O Bagger"
    },
    {
      "affiliations": [
        "HERVolution Therapeutics, Frederiksberg, Capital Region of Denmark, Denmark"
      ],
      "name": "Victoria Jaded"
    },
    {
      "affiliations": [
        "HERVolution Therapeutics, Frederiksberg, Capital Region of Denmark, Denmark"
      ],
      "name": "Anne-Marie Andersson"
    },
    {
      "affiliations": [
        "HERVolution Therapeutics, Frederiksberg, Capital Region of Denmark, Denmark",
        "Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Capital Region of Denmark, Denmark"
      ],
      "name": "Joana Daradoumis"
    },
    {
      "affiliations": [
        "HERVolution Therapeutics, Frederiksberg, Capital Region of Denmark, Denmark",
        "Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Capital Region of Denmark, Denmark"
      ],
      "name": "Amaia Vergara Bermejo"
    },
    {
      "affiliations": [
        "HERVolution Therapeutics, Frederiksberg, Capital Region of Denmark, Denmark",
        "Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Capital Region of Denmark, Denmark"
      ],
      "name": "Skandorff Isabella"
    },
    {
      "affiliations": [
        "HERVolution Therapeutics, Frederiksberg, Capital Region of Denmark, Denmark"
      ],
      "name": "Karen Nørgaard Nielsen"
    },
    {
      "affiliations": [
        "Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Capital Region of Denmark, Denmark"
      ],
      "name": "Faas Felix"
    },
    {
      "affiliations": [
        "Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Capital Region of Denmark, Denmark"
      ],
      "name": "Louise Turner"
    },
    {
      "affiliations": [
        "HERVolution Therapeutics, Frederiksberg, Capital Region of Denmark, Denmark"
      ],
      "name": "Tine Carola Gaziel"
    },
    {
      "affiliations": [
        "HERVolution Therapeutics, Frederiksberg, Capital Region of Denmark, Denmark",
        "Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Capital Region of Denmark, Denmark",
        "Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Capital Region of Denmark, Denmark"
      ],
      "name": "Peter J Holst"
    }
  ],
  "title": "646 Targeting the dark genome in solid tumors with IPT001: a virus-like particle (VLP)-based immunotherapy against HERV-K with checkpoint blockade synergy",
  "uid": "64ca75f4-1804-5c75-9795-c985f608b691"
}