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HBsAg-redirected T cells exhibit antiviral activity in HBV-infected human liver chimeric mice

  • Robert L. Kruse
    Affiliations
    Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, Texas, USA

    Center for Stem Cells and Regenerative Medicine, Baylor College of Medicine, Houston, Texas, USA

    Translational Biology and Molecular Medicine Program, Baylor College of Medicine, Houston, Texas, USA

    Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas, USA
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  • Thomas Shum
    Affiliations
    Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, Texas, USA

    Translational Biology and Molecular Medicine Program, Baylor College of Medicine, Houston, Texas, USA

    Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas, USA
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  • Haruko Tashiro
    Affiliations
    Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, Texas, USA
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  • Mercedes Barzi
    Affiliations
    Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, Texas, USA

    Center for Stem Cells and Regenerative Medicine, Baylor College of Medicine, Houston, Texas, USA
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  • Zhongzhen Yi
    Affiliations
    Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, Texas, USA
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  • Christina Whitten-Bauer
    Affiliations
    The Scripps Research Institute, La Jolla, California, USA
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  • Xavier Legras
    Affiliations
    Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, Texas, USA

    Center for Stem Cells and Regenerative Medicine, Baylor College of Medicine, Houston, Texas, USA
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  • Beatrice Bissig-Choisat
    Affiliations
    Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, Texas, USA

    Center for Stem Cells and Regenerative Medicine, Baylor College of Medicine, Houston, Texas, USA

    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
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  • Urtzi Garaigorta
    Affiliations
    The Scripps Research Institute, La Jolla, California, USA
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  • Author Footnotes
    * These authors contributed equally to the manuscript.
    Stephen Gottschalk
    Footnotes
    * These authors contributed equally to the manuscript.
    Affiliations
    Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, Texas, USA

    Translational Biology and Molecular Medicine Program, Baylor College of Medicine, Houston, Texas, USA

    Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA

    Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA

    Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA
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  • Author Footnotes
    * These authors contributed equally to the manuscript.
    Karl-Dimiter Bissig
    Correspondence
    Correspondence: Karl-Dimiter Bissig, MD, PhD, One Baylor Plaza, N1010, Houston, TX 77030, USA.
    Footnotes
    * These authors contributed equally to the manuscript.
    Affiliations
    Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, Texas, USA

    Center for Stem Cells and Regenerative Medicine, Baylor College of Medicine, Houston, Texas, USA

    Translational Biology and Molecular Medicine Program, Baylor College of Medicine, Houston, Texas, USA

    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA

    Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA
    Search for articles by this author
  • Author Footnotes
    * These authors contributed equally to the manuscript.
Published:April 06, 2018DOI:https://doi.org/10.1016/j.jcyt.2018.02.002

      Abstract

      Background

      Chronic hepatitis B virus (HBV) infection remains incurable. Although HBsAg-specific chimeric antigen receptor (HBsAg-CAR) T cells have been generated, they have not been tested in animal models with authentic HBV infection.

      Methods

      We generated a novel CAR targeting HBsAg and evaluated its ability to recognize HBV+ cell lines and HBsAg particles in vitro. In vivo, we tested whether human HBsAg-CAR T cells would have efficacy against HBV-infected hepatocytes in human liver chimeric mice.

      Results

      HBsAg-CAR T cells recognized HBV-positive cell lines and HBsAg particles in vitro as judged by cytokine production. However, HBsAg-CAR T cells did not kill HBV-positive cell lines in cytotoxicity assays. Adoptive transfer of HBsAg-CAR T cells into HBV-infected humanized mice resulted in accumulation within the liver and a significant decrease in plasma HBsAg and HBV-DNA levels compared with control mice. Notably, the fraction of HBV core–positive hepatocytes among total human hepatocytes was greatly reduced after HBsAg-CAR T cell treatment, pointing to noncytopathic viral clearance. In agreement, changes in surrogate human plasma albumin levels were not significantly different between treatment and control groups.

      Conclusions

      HBsAg-CAR T cells have anti-HBV activity in an authentic preclinical HBV infection model. Our results warrant further preclinical exploration of HBsAg-CAR T cells as immunotherapy for HBV.

      Key Words

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