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Cytotherapy. 2018 May;20(5):697-705. doi: 10.1016/j.jcyt.2018.02.002. Epub 2018 Apr 6.

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

Author information

1
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.
2
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.
3
Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, Texas, USA.
4
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.
5
The Scripps Research Institute, La Jolla, California, USA.
6
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.
7
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.
8
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. Electronic address: bissig@bcm.edu.

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.

KEYWORDS:

CAR T cells; adoptive immunotherapy; hepatitis B virus

PMID:
29631939
PMCID:
PMC6038120
[Available on 2019-05-01]
DOI:
10.1016/j.jcyt.2018.02.002

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