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

Robert L. Kruse, Thomas Shum, Haruko Tashiro, Mercedes Barzi, Zhongzhen Yi, Christina Whitten-Bauer, Xavier Legras, Beatrice Bissig-Choisat, Urtzi Garaigorta, Stephen Gottschalk, Karl Dimiter Bissig

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)697-705
Number of pages9
JournalCytotherapy
Volume20
Issue number5
DOIs
StatePublished - May 2018
Externally publishedYes

Keywords

  • CAR T cells
  • adoptive immunotherapy
  • hepatitis B virus

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Genetics(clinical)
  • Cell Biology
  • Cancer Research
  • Transplantation

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