HBsAg重新导向的T细胞在HBV感染的人肝嵌合体小鼠中表现出抗

StephenW

Cytotherapy. 2018 Apr 6. pii: S1465-3249(18)30037-9. doi: 10.1016/j.jcyt.2018.02.002. [Epub ahead of print]
HBsAg-redirected T cells exhibit antiviral activity in HBV-infected human liver chimeric mice.
Kruse RL1, Shum T2, Tashiro H3, Barzi M4, Yi Z3, Whitten-Bauer C5, Legras X4, Bissig-Choisat B6, Garaigorta U5, Gottschalk S7, Bissig KD8.
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: [email protected].

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.

Copyright © 2018 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.
KEYWORDS:

CAR T cells; adoptive immunotherapy; hepatitis B virus

PMID:
    29631939
DOI:
    10.1016/j.jcyt.2018.02.002

StephenW

Cytotherapy。 2018年4月6日，pii：S1465-3249（18）30037-9。 doi：10.1016 / j.jcyt.2018.02.002。 [电子版提前打印]
HBsAg重新导向的T细胞在HBV感染的人肝嵌合体小鼠中表现出抗病毒活性。
Kruse RL1，Shum T2，Tashiro H3，Barzi M4，Yi Z3，Whitten-Bauer C5，Legras X4，Bissig-Choisat B6，Garaigorta U5，Gottschalk S7，Bissig KD8。
作者信息

1
    美国得克萨斯州休斯敦贝勒医学院休斯敦卫理公会医院德克萨斯州儿童医院细胞与基因治疗中心;美国德克萨斯州休斯顿贝勒医学院干细胞与再生医学中心;美国德克萨斯州休斯敦贝勒医学院转化生物学和分子医学项目;美国德克萨斯州休斯顿贝勒医学院医学科学家培训计划。
2
    美国得克萨斯州休斯敦贝勒医学院休斯敦卫理公会医院德克萨斯州儿童医院细胞与基因治疗中心;美国德克萨斯州休斯敦贝勒医学院转化生物学和分子医学项目;美国德克萨斯州休斯顿贝勒医学院医学科学家培训计划。
3
    美国得克萨斯州休斯敦贝勒医学院休斯敦卫理公会医院德克萨斯州儿童医院细胞与基因治疗中心。
4
    美国得克萨斯州休斯敦贝勒医学院休斯敦卫理公会医院德克萨斯州儿童医院细胞与基因治疗中心;贝勒医学院干细胞与再生医学中心，美国得克萨斯州休斯敦。
五
    斯克里普斯研究所，美国加利福尼亚州拉霍亚市。
6
    美国得克萨斯州休斯敦贝勒医学院休斯敦卫理公会医院德克萨斯州儿童医院细胞与基因治疗中心;美国德克萨斯州休斯顿贝勒医学院干细胞与再生医学中心;美国德克萨斯州休斯顿贝勒医学院分子与细胞生物学系。
7
    美国得克萨斯州休斯敦贝勒医学院休斯敦卫理公会医院德克萨斯州儿童医院细胞与基因治疗中心;美国德克萨斯州休斯敦贝勒医学院转化生物学和分子医学项目;得克萨斯州儿童癌症中心，德克萨斯州儿童医院，贝勒医学院，美国得克萨斯州休斯敦;美国得克萨斯州休斯顿贝勒医学院儿科系;美国得克萨斯州休斯顿贝勒医学院病理与免疫学系。
8
    美国得克萨斯州休斯敦贝勒医学院休斯敦卫理公会医院德克萨斯州儿童医院细胞与基因治疗中心;美国德克萨斯州休斯顿贝勒医学院干细胞与再生医学中心;美国德克萨斯州休斯敦贝勒医学院转化生物学和分子医学项目;贝勒医学院分子与细胞生物学系，美国得克萨斯州休斯顿;美国得克萨斯州休斯敦贝勒医学院Dan L. Duncan癌症中心。电子地址：[email protected]。

抽象
背景：

慢性乙型肝炎病毒（HBV）感染仍然无法治愈。尽管已经产生了HBsAg特异性嵌合抗原受体（HBsAg-CAR）T细胞，但它们尚未在具有真正的HBV感染的动物模型中进行测试。
方法：

我们产生了一种新型的靶向HBsAg的CAR，并评估了它在体外识别HBV +细胞系和HBsAg颗粒的能力。在体内，我们测试人类HBsAg-CAR T细胞是否对人类肝脏嵌合小鼠中的HBV感染的肝细胞具有功效。
结果：

通过细胞因子产生来判断HBsAg-CAR T细胞在体外识别HBV阳性细胞系和HBsAg颗粒。然而，HBsAg-CAR T细胞在细胞毒性测定中不能杀死HBV阳性细胞系。将HBsAg-CAR T细胞过继转移至HBV感染的人源化小鼠中导致肝内蓄积，并且与对照小鼠相比，血浆HBsAg和HBV-DNA水平显着降低。值得注意的是，HBsAg-CAR T细胞治疗后，总人肝细胞中HBV核心阳性肝细胞的比例大大降低，表明非细胞病变病毒清除。同意的是，治疗组和对照组间替代人血浆白蛋白水平的变化没有显着差异。
结论：

HBsAg-CAR T细胞在真正的临床前HBV感染模型中具有抗HBV活性。我们的研究结果证明HBsAg-CAR T细胞作为HBV免疫治疗的进一步临床前研究。

Copyright©2018国际细胞治疗学会。由Elsevier Inc.出版。保留所有权利。
关键词：

CAR T细胞;过继免疫疗法;乙型肝炎病毒

结论：
    29631939
DOI：
    10.1016 / j.jcyt.2018.02.002