在免疫活性小鼠模型中评估完全人，乙型肝炎病毒特异性嵌

StephenW

Mol Ther. 2019 Feb 10. pii: S1525-0016(19)30042-5. doi: 10.1016/j.ymthe.2019.02.001. [Epub ahead of print]
Evaluation of a Fully Human, Hepatitis B Virus-Specific Chimeric Antigen Receptor in an Immunocompetent Mouse Model.
Festag MM1, Festag J1, Fräßle SP2, Asen T1, Sacherl J1, Schreiber S1, Mück-Häusl MA1, Busch DH3, Wisskirchen K4, Protzer U5.
Author information

1
    Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, 81675 Munich, Germany.
2
    Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, 81675 Munich, Germany.
3
    Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, 81675 Munich, Germany; German Center for Infection Research (DZIF), Munich partner site, 81675 Munich, Germany.
4
    Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, 81675 Munich, Germany; German Center for Infection Research (DZIF), Munich partner site, 81675 Munich, Germany. Electronic address: [email protected].
5
    Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, 81675 Munich, Germany; German Center for Infection Research (DZIF), Munich partner site, 81675 Munich, Germany. Electronic address: [email protected].

Abstract

Chimeric antigen receptor (CAR) T cell therapy is a promising novel therapeutic approach for cancer but also for chronic infection. We have developed a fully human, second-generation CAR directed against the envelope protein of hepatitis B virus on the surface of infected cells (S-CAR). The S-CAR contains a human B cell-derived single-chain antibody fragment and human immunoglobulin G (IgG) spacer, CD28- and CD3-signaling domains that may be immunogenic in mice. Because immunosuppression will worsen the clinical course of chronic hepatitis B, we aimed at developing a preclinical mouse model that is immunocompetent and mimics chronic hepatitis B but nevertheless allows evaluating efficacy and safety of a fully human CAR. The S-CAR grafted on T cells triggered antibody responses in immunocompetent animals, and a co-expressed human-derived safeguard, the truncated epidermal growth factor receptor (EGFRt), even induced B and T cell responses, both limiting the survival of S-CAR-grafted T cells. Total body irradiation and transfer of T cells expressing an analogous, signaling-deficient S-CAR decoy and the safeguard induced immune tolerance toward the human-derived structures. S-CAR T cells transferred after immune recovery persisted and showed long-lasting antiviral effector function. The approach we describe herein will enable preclinical studies of efficacy and safety of fully human CARs in the context of a functional immune system.

Copyright © 2019. Published by Elsevier Inc.
KEYWORDS:

AAV; CAR; HBV; T cell therapy; chimeric antigen receptor; immunocompetent mice; immunotherapy; rejection; scFv expression

PMID:
    30852138
DOI:
    10.1016/j.ymthe.2019.02.001

StephenW

Mol Ther。 2019年2月10日.pii：S1525-0016（19）30042-5。 doi：10.1016 / j.ymthe.2019.02.001。 [印刷前的电子版]
在免疫活性小鼠模型中评估完全人，乙型肝炎病毒特异性嵌合抗原受体。
Festag MM1，Festag J1，FräßleSP2，Asen T1，Sacherl J1，Schreiber S1，Mück-HäuslMA1，Busch DH3，Wisskirchen K4，Protzer U5。
作者信息

1
    慕尼黑工业大学病毒学研究所/ HelmholtzZentrumMünchen，81675 Munich，Germany。
2
    慕尼黑工业大学医学微生物学，免疫学和卫生学研究所，德国慕尼黑，81675。
3
    慕尼黑工业大学医学微生物学，免疫学和卫生研究所，德国慕尼黑，81675;德国感染研究中心（DZIF），慕尼黑合作伙伴网站，德国慕尼黑81675。
4
    慕尼黑工业大学病毒学研究所/ HelmholtzZentrumMünchen，81675 Munich，Germany;德国感染研究中心（DZIF），慕尼黑合作伙伴网站，德国慕尼黑81675。电子地址：[email protected]。
五
    慕尼黑工业大学病毒学研究所/ HelmholtzZentrumMünchen，81675 Munich，Germany;德国感染研究中心（DZIF），慕尼黑合作伙伴网站，德国慕尼黑81675。电子地址：[email protected]。

抽象

嵌合抗原受体（CAR）T细胞疗法是用于癌症但也用于慢性感染的有前途的新型治疗方法。我们开发了一种完全人类的第二代CAR，针对受感染细胞（S-CAR）表面的乙型肝炎病毒包膜蛋白。 S-CAR含有人B细胞衍生的单链抗体片段和人免疫球蛋白G（IgG）间隔区，CD28-和CD3-信号传导结构域，其在小鼠中可能是免疫原性的。由于免疫抑制会使慢性乙型肝炎的临床过程恶化，我们的目标是开发一种免疫活性的模型，模仿慢性乙型肝炎，但仍然可以评估完全人类CAR的疗效和安全性。在T细胞上移植的S-CAR在免疫活性动物中触发抗体反应，并且共表达的人源保护剂，即截短的表皮生长因子受体（EGFRt），甚至诱导B细胞和T细胞应答，两者都限制了S-的存活。 CAR移植的T细胞。全身照射和T细胞的转移，表达类似的，信号缺陷的S-CAR诱饵和对人源结构的安全诱导的免疫耐受。免疫恢复后转移的S-CAR T细胞持续存在，并显示出持久的抗病毒效应功能。我们在此描述的方法将能够在功能性免疫系统的背景下进行全人CAR的功效和安全性的临床前研究。

版权所有©2019。Elsevier Inc.出版
关键词：

AAV;汽车; HBV; T细胞疗法;嵌合抗原受体;免疫活性小鼠;免疫治疗;拒绝; scFv表达

结论：
    30852138
DOI：
    10.1016 / j.ymthe.2019.02.001