{
  "abstract": "Background: Immune desert/excluded tumors remain a major immunotherapeutic challenge. Herein, we aim to describe mechanistic insights of LOAd703, a novel tumor microenvironment gene engineering therapy targeting CD40 and 4–1BB, in patients with advanced solid cancer commonly associated with unresponsiveness to immunotherapy.\n\nMethods: The study evaluated blood and biopsy samples from pancreatic (n=29), colorectal (n=5), biliary (n=3), and ovarian cancer (n=4), treated with LOAd703 in combination with chemotherapy in a Swedish phase I/II clinical trial (NCT032259899).\n\nResults: Transcriptomic profiling of tumors before and after treatment initiation revealed induction of signatures known to predict immunotherapy responses and an enrichment for adaptive immune response pathways encompassing antigen-presentation and T-cell activation. In pancreatic cancer subanalysis, adaptive immune responses together with increased CD40 expression were associated with longer survival and CD40 appeared as a central node among upregulated immune biomarkers consistent with the mechanism of action of LOAd703. Treatment benefit was further associated with reduced expression of immunosuppressive and tumor-promoting factors both in tumors and peripheral blood. Systemically, treatment generated a Th1 profile in plasma, accompanied by an increase in effector/effector memory T cells and a reduction of regulatory T cells.\n\nConclusions: These findings support that intratumoral LOAd703 in combination with chemotherapy drives local and systemic immune remodeling in commonly immunotherapy-unresponsive tumors. Further, the treatment reprograms the tumor microenvironment to reduce tumor-promoting factors and immunosuppression.\n\nOne sentence summary: Targeting CD40 and 4–1BB with gene therapy in combination with chemotherapy induces immune responses associated with longer survival in pancreatic cancer.",
  "abstract_shown": true,
  "affiliations": [
    "Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden",
    "Department of Oncology, Uppsala University Hospital, Uppsala, Sweden",
    "Lokon Pharma AB, Uppsala, Sweden",
    "Department of Clinical Science, Intervention and Technology, Karolinska Hospital, Stockholm, Sweden"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Jessica Wenthe",
      "orcid": "0000-0003-4385-7568"
    },
    {
      "affs": [
        0
      ],
      "name": "Hanna Grauers Wiktorin",
      "orcid": "0000-0002-4412-5695"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Amanda Hahn",
      "orcid": "0009-0009-0796-2820"
    },
    {
      "affs": [
        0
      ],
      "name": "Sedigheh Naseri",
      "orcid": "0000-0002-3917-2622"
    },
    {
      "affs": [
        0
      ],
      "name": "Ahmed Calandigary"
    },
    {
      "affs": [
        0
      ],
      "name": "Luke White",
      "orcid": "0000-0003-4548-0661"
    },
    {
      "affs": [
        2
      ],
      "name": "Linda C Sandin"
    },
    {
      "affs": [
        2
      ],
      "name": "Clara Bernedal Nordström"
    },
    {
      "affs": [
        3
      ],
      "name": "Stephan Mielke"
    },
    {
      "affs": [
        0
      ],
      "name": "Tanja Lövgren",
      "orcid": "0000-0003-2170-0682"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Gustav J Ullenhag",
      "orcid": "0000-0003-4949-3267"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Angelica Loskog",
      "orcid": "0000-0001-8583-6138"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4s8xthm3zctkw.bib",
  "cited_by": 0,
  "doi": "10.1136/jitc-2026-016908",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13723919/",
  "id": "4s8xthm3zctkw",
  "issns": [
    "2051-1426"
  ],
  "landing_url": "https://doi.org/10.1136/jitc-2026-016908",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "1506"
    ],
    [
      "heading",
      "2438"
    ],
    [
      "heading",
      "Oncolytic and Local Immunotherapy"
    ],
    [
      "heading",
      "Original Research"
    ],
    [
      "openalex",
      "2730|Cancer Immunotherapy and Biomarkers"
    ]
  ],
  "openalex": "W7224112963",
  "pdf_url": "https://jitc.bmj.com/content/14/10/e016908.full.pdf",
  "pmcid": "PMC13723919",
  "pmid": "42951313",
  "published": "2026-10-28",
  "publisher": "BMJ Publishing Group",
  "ris": "https://research.draconitic.com/paper/4s8xthm3zctkw.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T12:22:28Z",
      "native_id": "PMC13723919",
      "source": "pmc",
      "url": "https://doi.org/10.1136/jitc-2026-016908"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|Cancer Immunotherapy and Biomarkers",
      "subfield": "oncology"
    }
  ],
  "title": "Immunostimulatory gene therapy with chemotherapy remodels pancreatic tumors and induces immune signatures associated with prolonged survival",
  "title_text": "Immunostimulatory gene therapy with chemotherapy remodels pancreatic tumors and induces immune signatures associated with prolonged survival",
  "type": "peer-reviewed",
  "updated_at": "2026-11-05T12:20:39Z",
  "url": "https://research.draconitic.com/paper/4s8xthm3zctkw",
  "venue": "Journal for Immunotherapy of Cancer",
  "versions": []
}