{
  "abstract": "Background Oncolytic viruses encoding transgene payloads represent a tractable single-agent approach to targeted delivery of immunomodulatory therapies to tumors and have emerged as a promising modality in cancer therapy. TROCEPT is a next-generation genetically modified adenovirus type-5 rationally designed to overcome the limitations of existing IV delivered viruses to significantly increase tumor exposure. TROCEPT is uniquely de-targeted to avoid uptake by healthy cells, including the liver, by removal of normal cell tropisms, and is re-targeted to specifically infect and replicate in tumor cells that express αvβ6 integrin which is highly expressed in epithelial cancers. ATTR-01 is a first-in-class transgene modified variant of TROCEPT that, following infection of permissive tumor cells, expresses an anti-PD-L1 antibody payload. Intratumoral expression of the anti-PD-L1 checkpoint inhibitor locally, rather than via systemic delivery by IV infusion, may lead to higher local (tumor) concentrations of the drug and avoid exhaustion of systemic T cells, thereby increasing efficacy and reducing off tumor toxicity.Methods In vitro normal and tumor cell biology and immunohistochemistry assays and Intravenous administration of TROCEPT or control viruses in murine healthy and human tumor xenograft in vivo pharmacodynamic and short-term toxicity studies.Results In vitro experiments demonstrate that viral replication, transgene expression and oncolytic cell death following infection with ATTR-01 is highly selective for αvβ6 integrin positive tumor cells compared to a panel of normal human primary cells. Intravenous delivery in in vivo human tumor xenograft mouse models demonstrate virus delivery, replication, and transgene expression in the tumor. Tumor regression and survival was observed in all five tumor indications tested; ovarian, pancreatic, bladder, colorectal and lung tumors. In comparison to the parental Ad5 virus, the engineering of ATTR-01 led to more viral delivery to the tumor and less delivery and thereby toxicity to normal tissues including liver. A greater than 100-fold improved tumor-to-liver ratio was observed with ATTR-01 compared to parental Ad5. No liver enzyme or inflammatory cytokine changes were observed with ATTR-01 even at the top dose equivalent to 3x1014 viral particles.Conclusions This data demonstrates tumor selectivity, anti-tumor activity and a positive non-clinical safety profile of ATTR-01. A phase 1 study, ATTEST, is evaluating safety and preliminary efficacy of intravenous delivery of ATTR-01 in patients with selected epithelial tumors expressing high levels of the target αvβ6 integrin, including non-small cell lung, urothelial, head and neck, pancreatic, endometrial and cholangiocarcinoma in multiple sites in UK.Ethics Approval Studies were carried out with appropriate ethical approval and Home Office licence references 19/WS/0164, 23/PR/0221 and PP1144128Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal",
  "authors": [
    {
      "affiliations": [
        "Accession Therapeutics, Oxford, UK"
      ],
      "name": "Rahul C Khanolkar"
    },
    {
      "affiliations": [
        "Accession Therapeutics, Oxford, UK"
      ],
      "name": "James A Davies"
    },
    {
      "affiliations": [
        "Accession Therapeutics, Oxford, UK"
      ],
      "name": "Alexander T Baker"
    },
    {
      "affiliations": [
        "Accession Therapeutics, Oxford, UK"
      ],
      "name": "Thomas A Webb"
    },
    {
      "affiliations": [
        "Accession Therapeutics, Oxford, UK"
      ],
      "name": "S Shahreza"
    },
    {
      "affiliations": [
        "Accession Therapeutics, Oxford, UK"
      ],
      "name": "Navneet Boparan"
    },
    {
      "affiliations": [
        "Cardiff University, Cardiff, UK"
      ],
      "name": "H Uusi-Kerttula"
    },
    {
      "affiliations": [
        "Accession Therapeutics, Oxford, UK"
      ],
      "name": "Lucy M Williams"
    },
    {
      "affiliations": [
        "Accession Therapeutics, Oxford, UK"
      ],
      "name": "Emma Henderson"
    },
    {
      "affiliations": [
        "Accession Therapeutics, Oxford, UK"
      ],
      "name": "Samantha L Moore"
    },
    {
      "affiliations": [
        "Accession Therapeutics, Oxford, UK"
      ],
      "name": "Johanne M Pentier"
    },
    {
      "affiliations": [
        "Accession Therapeutics, Oxford, UK"
      ],
      "name": "Bent K Jakobsen"
    },
    {
      "affiliations": [
        "Accession Therapeutics, Oxford, UK"
      ],
      "name": "Alan Parker"
    },
    {
      "affiliations": [
        "Accession Therapeutics, Oxford, UK"
      ],
      "name": "Dave Cole"
    },
    {
      "affiliations": [
        "Accession Therapeutics, Oxford, UK"
      ],
      "name": "Andrew B Gerry"
    }
  ],
  "title": "687 TROCEPT A tumor targeted precision immunovirotherapy enabling αvβ6 integrin positive tumor localized expression of an immune checkpoint inhibitor following intravenous delivery",
  "uid": "fd321666-bb35-5acb-a0b7-2fc5ecf70456"
}