Robert L Kruse1, Thomas Shum2, Haruko Tashiro3, Mercedes Barzi4, Zhongzhen Yi3, Christina Whitten-Bauer5, Xavier Legras4, Beatrice Bissig-Choisat6, Urtzi Garaigorta5, Stephen Gottschalk7, Karl-Dimiter Bissig8. 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.
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.
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