{
  "abstract": "Background Glioblastoma (GBM) is an aggressive brain tumor associated with poor outcome and limited treatment options. Chimeric antigen receptor (CAR) T cells targeting cell surface antigens were shown to induce tumor regression in patients with GBM, although efficacy was transient. To broaden the range of tumor-restricted antigens, we developed CAR T cells targeting Tenascin-C (TNC), a secreted extracellular matrix protein that is overexpressed in GBM and plays a critical role in tumor progression.Methods Second-generation CAR T cells were engineered to target the alternatively spliced fibronectin type III (FNIII)-D domain of TNC using a single-chain variable fragment isolated from the R6N antibody and coupled to a CD28 costimulatory domain. TNC-CAR T cells were evaluated in vitro for antigen specificity, activation, and cell proliferation using TNC-expressing patient-derived GBM cell lines cultured as adherent cells or as neurospheres. Reactivity toward purified TNC protein, tumor supernatant, and ex vivo patient tumor samples was also assessed. Cytotoxic CAR T-cell activity was tested against TNC-positive and TNC-negative GBM cell lines, including bystander effects mediated by secreted TNC. In vivo efficacy and safety were determined in NOD scid gamma mice bearing patient-derived GBM tumors.Results TNC-CAR T cells demonstrated activation when exposed to TNC-positive GBM cells, cell-derived supernatants, or purified TNC protein. They exhibited potent cytotoxicity against TNC-expressing, GBM-derived adherent cells and neurospheres, and induced bystander killing of TNC-negative cells in the presence of either TNC-secreting cells or purified TNC. In vivo, TNC-CAR T cells efficiently infiltrated tumors, triggered cancer cell apoptosis, and significantly extended survival of mice bearing patient-derived GBM, with no evidence of off-tumor toxicity. Notably, TNC-CAR T cells were activated exclusively in the presence of tumor samples and showed no reactivity toward patient-derived non-tumor tissues.Conclusions Targeting the alternatively spliced FNIII-D domain of TNC with CAR T cells offers a promising therapeutic approach for GBM. TNC-CAR T cells demonstrated specific tumor recognition, robust antitumor activity and the ability to induce bystander effects mediated by secreted TNC. Their efficacy in preclinical models, combined with a favorable safety profile, underscores their potential for clinical translation.",
  "authors": [
    {
      "affiliations": [
        "Brain Tumor and Immune Cell Engineering Laboratory, Faculty of Medicine, University of Geneva, Geneva, Switzerland"
      ],
      "name": "Jana de Sostoa"
    },
    {
      "affiliations": [
        "Brain Tumor and Immune Cell Engineering Laboratory, Faculty of Medicine, University of Geneva, Geneva, Switzerland"
      ],
      "name": "Eliana Marinari"
    },
    {
      "affiliations": [
        "Brain Tumor and Immune Cell Engineering Laboratory, Faculty of Medicine, University of Geneva, Geneva, Switzerland"
      ],
      "name": "Martin Pedard"
    },
    {
      "affiliations": [
        "Brain Tumor and Immune Cell Engineering Laboratory, Faculty of Medicine, University of Geneva, Geneva, Switzerland"
      ],
      "name": "Valérie Widmer"
    },
    {
      "affiliations": [
        "Brain Tumor and Immune Cell Engineering Laboratory, Faculty of Medicine, University of Geneva, Geneva, Switzerland"
      ],
      "name": "Suzel Davanture"
    },
    {
      "affiliations": [
        "Division of Neurosurgery, Department of Clinical Neurosciences, Geneva University Hospitals, Geneva, Switzerland"
      ],
      "name": "Karl Schaller"
    },
    {
      "affiliations": [
        "Centre des Thérapies Expérimentales, Immune Landscape Laboratory, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland"
      ],
      "name": "Stephanie Tissot"
    },
    {
      "affiliations": [
        "Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne, Lausanne, Switzerland"
      ],
      "name": "Michele De Palma"
    },
    {
      "affiliations": [
        "Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland",
        "Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland"
      ],
      "name": "Benita Wolf"
    },
    {
      "affiliations": [
        "INSERM U1109, The Tumor Microenvironment Laboratory, University of Strasbourg, Strasbourg, France"
      ],
      "name": "Gertraud Orend"
    },
    {
      "affiliations": [
        "Brain Tumor and Immune Cell Engineering Laboratory, Faculty of Medicine, University of Geneva, Geneva, Switzerland"
      ],
      "name": "Valérie Dutoit"
    },
    {
      "affiliations": [
        "Brain Tumor and Immune Cell Engineering Laboratory, Faculty of Medicine, University of Geneva, Geneva, Switzerland",
        "Department of Oncology, Geneva University Hospitals, Geneva, Switzerland"
      ],
      "name": "Denis Migliorini"
    }
  ],
  "title": "Targeting the extracellular matrix with Tenascin-C-specific CAR T cells extends survival in preclinical models of glioblastoma",
  "uid": "ac478af1-f218-59da-a86e-a03c3fc7aa7c"
}