{
  "abstract": "Background Pancreatic ductal adenocarcinoma (PDAC) remains largely refractory to chimeric antigen receptor (CAR)-T cell therapy. Insufficient T cell infiltration, a highly immunosuppressive microenvironment, and antigen loss pose major challenges for CAR-T cell therapy.Methods We investigated therapeutic synergies of synthetic 5′-triphosphate RNA (3p-RNA), an agonist of the cytoplasmic double-stranded RNA sensor Retinoic Acid Inducible Gene I (RIG-I), and CAR-T cell therapy using syngeneic and human xenograft PDAC models. Tumor growth, chemokine secretion, immune-cell composition, CAR-T persistence, and endogenous T cell responses were assessed by flow cytometry, multiplex cytokine arrays, Enzyme-linked Immunospot (ELISpot), and vaccination-challenge.Results 3p-RNA provoked rapid type I interferon accompanied with chemokine ligand CCL5 and CXCL9/10/11 secretion, creating chemokine gradients that recruited chemokine receptor CCR5 +/CXCR3+ CAR-T cells into tumors. RIG-I activation enhanced CAR-T cell proliferation, activity, and CAR-T persistence. Combination therapy eradicated established tumors in 60%–70% of mice, whereas either monotherapy was largely ineffective. Cured animals rejected CAR antigen-negative tumor cell rechallenge, demonstrating antigen-spreading and endogenous T cell responses.Conclusions Intratumoral RIG-I priming reprograms the PDAC microenvironment, transforming a non-responsive cancer into a CAR-T-permissive one, supporting durable, poly-antigenic immunity. These findings position 3p-RNA as a rapid, clinically tractable co-therapy to extend CAR-T efficacy to solid tumors.",
  "authors": [
    {
      "affiliations": [
        "Institute of Clinical Pharmacology, LMU University Hospital, LMU Munich, Munich, Germany"
      ],
      "name": "Anne Marie Senz"
    },
    {
      "affiliations": [
        "Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany"
      ],
      "name": "Bruno L Cadilha"
    },
    {
      "affiliations": [
        "Institute of Clinical Pharmacology, LMU University Hospital, LMU Munich, Munich, Germany"
      ],
      "name": "Julia Teppert"
    },
    {
      "affiliations": [
        "Institute of Clinical Pharmacology, LMU University Hospital, LMU Munich, Munich, Germany"
      ],
      "name": "Simone Formisano"
    },
    {
      "affiliations": [
        "Institute of Clinical Pharmacology, LMU University Hospital, LMU Munich, Munich, Germany"
      ],
      "name": "Charlotte Marx"
    },
    {
      "affiliations": [
        "Institute of Clinical Pharmacology, LMU University Hospital, LMU Munich, Munich, Germany"
      ],
      "name": "Theo Lorenzini"
    },
    {
      "affiliations": [
        "Institute of Clinical Pharmacology, LMU University Hospital, LMU Munich, Munich, Germany",
        "Department of Medicine II, LMU University Hospital, LMU Munich, Munich, Germany"
      ],
      "name": "Daniel F R Boehmer"
    },
    {
      "affiliations": [
        "Institute of Clinical Pharmacology, LMU University Hospital, LMU Munich, Munich, Germany"
      ],
      "name": "Christine Hoerth"
    },
    {
      "affiliations": [
        "Institute of Clinical Pharmacology, LMU University Hospital, LMU Munich, Munich, Germany"
      ],
      "name": "Simon Delahais"
    },
    {
      "affiliations": [
        "Institute of Clinical Pharmacology, LMU University Hospital, LMU Munich, Munich, Germany",
        "German Cancer Consortium (DKTK), a partnership between LMU Klinikum and DKFZ, Heidelberg, Germany",
        "Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum Munchen Deutsches Forschungszentrum fur Gesundheit und Umwelt Gmbh, Neuherberg, Germany"
      ],
      "name": "Stefan Endres"
    },
    {
      "affiliations": [
        "Institute of Innate Immunity, University Hospital Bonn, Bonn, Germany"
      ],
      "name": "Peter Duewell"
    },
    {
      "affiliations": [
        "Institute of Clinical Pharmacology, LMU University Hospital, LMU Munich, Munich, Germany"
      ],
      "name": "Max Schnurr"
    },
    {
      "affiliations": [
        "Institute of Clinical Pharmacology, LMU University Hospital, LMU Munich, Munich, Germany",
        "German Cancer Consortium (DKTK), a partnership between LMU Klinikum and DKFZ, Heidelberg, Germany",
        "Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum Munchen Deutsches Forschungszentrum fur Gesundheit und Umwelt Gmbh, Neuherberg, Germany",
        "German Center for Lung Research (DZL), Munich, Germany"
      ],
      "name": "Sebastian Kobold"
    },
    {
      "affiliations": [
        "Institute of Clinical Pharmacology, LMU University Hospital, LMU Munich, Munich, Germany"
      ],
      "name": "Lars M Koenig"
    }
  ],
  "title": "RIG-I agonists promote antigen-spreading and facilitate durable CAR-T responses in pancreatic ductal adenocarcinoma",
  "uid": "4a5110d3-463d-5c5f-8a4f-f1619aacd802"
}