{
  "abstract": "Background We previously showed that oncolytic virotherapy delivered by isolated limb perfusion (ILP), combined with immune checkpoint inhibition, prevents both local tumor progression and systemic metastases in an animal sarcoma model.Methods We describe a first-in-human phase I/II trial combining oncolytic herpes simplex virus, talimogene laherparepvec (T-VEC), with melphalan and tumor necrosis factor-alpha delivered by ILP, in patients with locally advanced sarcoma or melanoma.Results T-VEC/ILP is well tolerated, with an overall response rate of 53% in all patients and 44% in sarcoma. Importantly, we report durable complete responses in sarcoma subtypes usually unresponsive to ILP. Translational analysis of longitudinal tumor and blood samples showed that T-VEC induced an inflammatory gene expression profile within injected tumors, which was more sustained in sarcoma than in melanoma. In relation to clinical outcome, responding patients with sarcoma showed a greater increase in gene expression for interferon response after virus treatment than non-responding patients. Analysis of the T-cell repertoire (TCR) in tumor and blood showed that clonality was higher in the tumor, but lower in the blood, in responders following virotherapy, suggesting that virus treatment may expand intratumoral T-cell clones that recognize tumor and/or viral antigens. Increased TCR diversity in the blood was suggestive of a systemic immune response.Conclusions These clinical and translational findings support the further development of oncolytic virotherapy/ILP combinations to activate both systemic and local antitumor immunity, including in tumor types such as sarcoma, which are largely refractory to current treatment with immunotherapy.",
  "authors": [
    {
      "affiliations": [
        "The Royal Marsden NHS Foundation Trust, London, UK",
        "The Institute of Cancer Research, London, England, UK"
      ],
      "name": "Andrew J Hayes"
    },
    {
      "affiliations": [
        "The Royal Marsden NHS Foundation Trust, London, UK",
        "The Institute of Cancer Research, London, England, UK"
      ],
      "name": "Emma J Davies"
    },
    {
      "affiliations": [
        "The Royal Marsden NHS Foundation Trust, London, UK",
        "The Institute of Cancer Research, London, England, UK"
      ],
      "name": "Michelle Wilkinson"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, England, UK",
        "Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark"
      ],
      "name": "Henry G Smith"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, England, UK"
      ],
      "name": "Pablo Nenclares"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, England, UK",
        "Integrated Pathology Unit, The Royal Marsden NHS Foundation Trust, London, UK"
      ],
      "name": "Tom Lund"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, England, UK"
      ],
      "name": "Adrian Larkeryd"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, England, UK"
      ],
      "name": "Elizabeth Appleton"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, England, UK"
      ],
      "name": "Emmanuel Christian Patin"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, England, UK"
      ],
      "name": "Malin Pedersen"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, England, UK"
      ],
      "name": "Antonio Rullan"
    },
    {
      "affiliations": [
        "The Royal Marsden NHS Foundation Trust, London, UK",
        "The Institute of Cancer Research, London, England, UK"
      ],
      "name": "Hesham S Mohamed"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, England, UK"
      ],
      "name": "Lauren Aronson"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, England, UK"
      ],
      "name": "Jessica Murphy"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, England, UK"
      ],
      "name": "Lorna Grove"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, England, UK"
      ],
      "name": "David Mansfield"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, England, UK"
      ],
      "name": "Martin Mclaughlin"
    },
    {
      "affiliations": [
        "The Royal Marsden NHS Foundation Trust, London, UK",
        "The Institute of Cancer Research, London, England, UK"
      ],
      "name": "Kevin J Harrington"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, England, UK"
      ],
      "name": "Alan Melcher"
    }
  ],
  "title": "Addition of oncolytic virotherapy to clinical isolated limb perfusion for melanoma and sarcoma activates antitumor immunity",
  "uid": "301aa523-669b-5019-b41a-d656be67d4c2"
}