TY - JOUR
T1 - HBsAg-redirected T cells exhibit antiviral activity in HBV-infected human liver chimeric mice
AU - Kruse, Robert L.
AU - Shum, Thomas
AU - Tashiro, Haruko
AU - Barzi, Mercedes
AU - Yi, Zhongzhen
AU - Whitten-Bauer, Christina
AU - Legras, Xavier
AU - Bissig-Choisat, Beatrice
AU - Garaigorta, Urtzi
AU - Gottschalk, Stephen
AU - Bissig, Karl Dimiter
N1 - Funding Information:
We thank James Broughman for assistance with electron microscopy and Stefan Wieland and Catherine Gillespie for critical comments on the manuscript. This work was supported by the National Institutes of Heath grants R01AI094409 , R01HL134510 , T32DK060445 and 5T32HL092332 ; the Texas Hepatocellular Carcinoma Consortium ( CPRIT RP150587 ); and the Diana Helis Henry and Adrienne Helis Malvin Medical Research Foundations . The Dan L. Duncan Cancer Center is supported by P30-CA125123. The Integrated Microscopy Core at the Texas Medical Center Digestive Disease Center is supported by P30-DK56338.
Funding Information:
We thank James Broughman for assistance with electron microscopy and Stefan Wieland and Catherine Gillespie for critical comments on the manuscript. This work was supported by the National Institutes of Heath grants R01AI094409, R01HL134510, T32DK060445 and 5T32HL092332; the Texas Hepatocellular Carcinoma Consortium (CPRIT RP150587); and the Diana Helis Henry and Adrienne Helis Malvin Medical Research Foundations. The Dan L. Duncan Cancer Center is supported by P30-CA125123. The Integrated Microscopy Core at the Texas Medical Center Digestive Disease Center is supported by P30-DK56338.
Publisher Copyright:
© 2018 International Society for Cellular Therapy
PY - 2018/5
Y1 - 2018/5
N2 - 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.
AB - 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.
KW - adoptive immunotherapy
KW - CAR T cells
KW - hepatitis B virus
UR - http://www.scopus.com/inward/record.url?scp=85044990593&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85044990593&partnerID=8YFLogxK
U2 - 10.1016/j.jcyt.2018.02.002
DO - 10.1016/j.jcyt.2018.02.002
M3 - Article
C2 - 29631939
AN - SCOPUS:85044990593
SN - 1465-3249
VL - 20
SP - 697
EP - 705
JO - Cytotherapy
JF - Cytotherapy
IS - 5
ER -