{
  "abstract": "Background Solid tumors comprise approximately 60% of all pediatric cancers. Relapsed or refractory tumors of the central nervous system (CNS), such as atypical teratoid/rhabdoid tumors (AT/RTs), are the leading cause of death in children with cancer. Claudin 6 (CLDN6)-specific chimeric antigen receptor (CAR) T cells have demonstrated activity in preclinical and clinical studies in various solid adult cancers. However, the suitability of CLDN6 as a target in pediatric tumors and their susceptibility to CAR T-cell therapy has yet to be established. This study aimed to evaluate the suitability of CLDN6 as a target for CAR T-cell therapy of pediatric solid tumors.Methods Immunohistochemical CLDN6 expression was assessed in fetal normal tissues (n=91), pediatric normal tissues (n=157), and two sets of pediatric tumor tissues (n=527 and n=49) using a combined score that includes the percentage of stained cells with a 4-point intensity scale (0 to 3+). The antitumor activity of CLDN6 RNA-transduced CAR T cells against AT/RT cell lines was assessed with in vitro assays and in immunodeficient NOD-SCID-γc–/– (NSG) mouse models bearing orthotopic xenograft tumors.Results Membranous CLDN6 expression, as detected by immunohistochemistry, was widely observed in fetal tissues but was absent in almost all non-malignant pediatric tissues, except for very rare, scattered cells with 1+ to 2+ intensity in kidney, pancreas, pituitary, and salivary gland tissues. Membranous CLDN6 expression was frequently detected in a subset of the pediatric tumor entities, including germ cell tumors (93% of samples with CLDN6-positive cells), nephroblastoma (64%), extracranial malignant rhabdoid tumors (50%), and AT/RTs (39%). In CLDN6-positive samples, CLDN6 was generally expressed with 2+ or 3+ intensity in substantial proportions of the cancer cells. Strong CLDN6 expression was also detected in single samples of hepatoblastoma, Ewing sarcoma/other embryonal tumors, and osteosarcoma.In experimental models, CLDN6-CAR T cells led to antigen-specific killing of endogenously CLDN6-expressing AT/RT cell lines in vitro and exhibited potent and specific antitumor activity in mice bearing orthotopic CLDN6-expressing AT/RT xenograft tumors.Conclusions These results support CLDN6 as an oncofetal cell-surface antigen that may be suitable for CAR T-cell targeting in pediatric solid tumors, including those of the CNS.",
  "authors": [
    {
      "affiliations": [
        "Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA",
        "Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA",
        "Center for Data Driven Discovery in Biomedicine (D3b), Children’s Hospital of Philadelphia, Philadelphia, PA, USA"
      ],
      "name": "Peter J Madsen"
    },
    {
      "affiliations": [
        "BioNTech SE, Mainz, Germany",
        "TUM School of Medicine and Health, Technical University of Munich, Munich, Germany"
      ],
      "name": "Anna Melissa Schlitter"
    },
    {
      "affiliations": [
        "BioNTech SE, Mainz, Germany"
      ],
      "name": "Carina Flemmig"
    },
    {
      "affiliations": [
        "Center for Data Driven Discovery in Biomedicine (D3b), Children’s Hospital of Philadelphia, Philadelphia, PA, USA"
      ],
      "name": "Conor Dickson"
    },
    {
      "affiliations": [
        "Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA"
      ],
      "name": "Kyra Harvey"
    },
    {
      "affiliations": [
        "Center for Data Driven Discovery in Biomedicine (D3b), Children’s Hospital of Philadelphia, Philadelphia, PA, USA"
      ],
      "name": "Cullen Wilson"
    },
    {
      "affiliations": [
        "Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA"
      ],
      "name": "Ezra Beaubien"
    },
    {
      "affiliations": [
        "Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA"
      ],
      "name": "Luke Patterson"
    },
    {
      "affiliations": [
        "Center for Data Driven Discovery in Biomedicine (D3b), Children’s Hospital of Philadelphia, Philadelphia, PA, USA"
      ],
      "name": "Allison Stern"
    },
    {
      "affiliations": [
        "Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA"
      ],
      "name": "Crystal Griffin"
    },
    {
      "affiliations": [
        "Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA"
      ],
      "name": "Nikhil Joshi"
    },
    {
      "affiliations": [
        "Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA"
      ],
      "name": "Sreehita Hajeebu"
    },
    {
      "affiliations": [
        "Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"
      ],
      "name": "Daniel Martinez"
    },
    {
      "affiliations": [
        "Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA",
        "Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA",
        "Center for Data Driven Discovery in Biomedicine (D3b), Children’s Hospital of Philadelphia, Philadelphia, PA, USA"
      ],
      "name": "Phillip B Storm"
    },
    {
      "affiliations": [
        "Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA",
        "Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA",
        "Center for Data Driven Discovery in Biomedicine (D3b), Children’s Hospital of Philadelphia, Philadelphia, PA, USA"
      ],
      "name": "Adam C Resnick"
    },
    {
      "affiliations": [
        "Departments of Gynecology and Obstetrics, and Comprehensive Cancer Center, Hannover Medical School, Hannover, Germany"
      ],
      "name": "Peter Hillemanns"
    },
    {
      "affiliations": [
        "Department of Paediatric Haematology and Oncology, Hannover Medical School, Hannover, Germany"
      ],
      "name": "Martin Stanulla"
    },
    {
      "affiliations": [
        "Department of Pediatric Hematology/Oncology/Hemostaseology, Center for Pediatric and Adolescent Medicine, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany",
        "University Cancer Center Mainz (UCT Mainz), University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany"
      ],
      "name": "Jörg Faber"
    },
    {
      "affiliations": [
        "Department of Pediatric Hematology/Oncology/Hemostaseology, Center for Pediatric and Adolescent Medicine, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany",
        "University Cancer Center Mainz (UCT Mainz), University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany"
      ],
      "name": "Arthur Wingerter"
    },
    {
      "affiliations": [
        "Institute of Pathology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany",
        "Translational Oncology (TRON gGmbH) at the University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany",
        "Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany"
      ],
      "name": "Matthias Martin Gaida"
    },
    {
      "affiliations": [
        "BioNTech SE, Mainz, Germany"
      ],
      "name": "Saskia Holtemeyer"
    },
    {
      "affiliations": [
        "BioNTech SE, Mainz, Germany"
      ],
      "name": "Mark Laible"
    },
    {
      "affiliations": [
        "BioNTech SE, Mainz, Germany"
      ],
      "name": "Anja Feldner"
    },
    {
      "affiliations": [
        "BioNTech SE, Mainz, Germany"
      ],
      "name": "Florian Frohns"
    },
    {
      "affiliations": [
        "BioNTech Cell and Gene Therapies GmbH, Mainz, Germany"
      ],
      "name": "João H Duarte"
    },
    {
      "affiliations": [
        "BioNTech SE, Mainz, Germany"
      ],
      "name": "Bruno Valentin Sinn"
    },
    {
      "affiliations": [
        "BioNTech SE, Mainz, Germany"
      ],
      "name": "Stefan Wöll"
    },
    {
      "affiliations": [
        "BioNTech SE, Mainz, Germany",
        "University Cancer Center Mainz (UCT Mainz), University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany",
        "Helmholtz-Institute for Translational Oncology Mainz (HI-TRON Mainz), German Cancer Research Center (DKFZ), Mainz, Germany"
      ],
      "name": "Ugur Sahin"
    },
    {
      "affiliations": [
        "BioNTech SE, Mainz, Germany",
        "Helmholtz-Institute for Translational Oncology Mainz (HI-TRON Mainz), German Cancer Research Center (DKFZ), Mainz, Germany"
      ],
      "name": "Özlem Türeci"
    },
    {
      "affiliations": [
        "Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA",
        "Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"
      ],
      "name": "Jessica B Foster"
    }
  ],
  "title": "Claudin 6 is a suitable target for CAR T-cell therapy in atypical teratoid/rhabdoid brain tumors and other pediatric solid tumors",
  "uid": "8b3dc795-f8cb-5b59-8044-16b5462a77e2"
}