实践方法 使用重定向乙型肝炎病毒的T细胞的肝细胞癌的免疫

StephenW

Mol Ther Nucleic Acids. 2013;2:e114. doi: 10.1038/mtna.2013.43. Epub  2016 Dec 13.
A Practical Approach to Immunotherapy of Hepatocellular Carcinoma Using T Cells Redirected Against Hepatitis B Virus.Koh S1, Shimasaki N2, Suwanarusk R3, Ho ZZ4, Chia A4, Banu N4, Wu Howland S3, Ong AS3, Gehring AJ5, Stauss H6, Renia L3, Sällberg M7, Campana D2, Bertoletti A8.
Author information

• 1Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, (A*STAR), Singapore; Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Stockholm, Sweden.
• 2Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
• 3Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore.
• 4Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, (A*STAR), Singapore.
• 5Department of Molecular Microbiology and Immunology, Saint Louis University Medical Center, St. Louis, Missouri, USA.
• 6Department of Immunology, Royal Free Hospital, London, UK.
• 7Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Stockholm, Sweden.
• 8Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, (A*STAR), Singapore; Emerging Infectious Diseases Program, Duke NUS Graduate Medical School, Singapore. Electronic address: [email protected].
  

AbstractHepatocellular carcinoma (HCC) cells often have hepatitis B virus (HBV)-DNA integration and can be targeted by HBV-specific T cells. The use of viral vectors to introduce exogenous HBV-specific T-cell receptors (TCR) on T cells to redirect their specificity is complex and expensive to implement in clinical trials. Moreover, it raises safety concerns related to insertional mutagenesis and potential toxicity of long-lived HBV-specific T cells in patients with persistent infection. To develop a more practical and safer approach to cell therapy of HCC, we used electroporation of mRNA encoding anti-HBV TCR. Approximately 80% of CD8+ T cells expressed functional HBV TCR 24 hours postelectroporation, an expression efficiency much higher than that obtained by retroviral transduction (~18%). Antigen-specific cytokine production of electroporated T cells was efficient within 72-hour period, after which the redirected T cells lost their HBV-specific function. Despite this transient functionality, the TCR-electroporated T cells efficiently prevented tumor seeding and suppressed the growth of established tumors in a xenograft model of HCC. Finally, we established a method for large-scale TCR mRNA electroporation that yielded large numbers of highly functional clinical-grade anti-HBV T cells. This method represents a practical approach to cell therapy of HCC and its inherently self-limiting toxicity suggests potential for application in other HBV-related pathologies.

Molecular Therapy-Nucleic Acids is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/.

KEYWORDS: TCR gene therapy; hepatitis B virus; hepatocellular carcinoma; mRNA electroporation

PMID:28173945DOI:10.1038/mtna.2013.43

StephenW

Mol Ther Nucleic Acids。 2013; 2：e114。 Doi：10.1038 / mtna.2013.43。 2016年12月13日。
A Practical Approach to Immunotherapy of Hepatocellular Carcinoma Using T Cells Redirected Against Hepatitis B Virus。
苏梅S1，Shimasaki N2，Suwanarusk R3，何ZZ4，孙家A4，巴努N4，吴豪兰S3，翁​​AS3，Gehring集团AJ5，斯斯H6，Renia L3，SällbergM7，坎帕纳D2，BERTOLETTI A8。
作者信息

1新加坡临床科学研究所，科学技术研究机构（A * STAR），新加坡;临床微生物学司，Karolinska Institutet，斯德哥尔摩，瑞典实验室医学部。
2新加坡国立大学医学院林勇林儿科小儿科。
3新加坡免疫学网络（SIgN），科学技术研究机构（A * STAR），新加坡。
4新加坡临床科学研究所，科学，技术和研究机构（A * STAR），新加坡。
5 Department of Molecular Microbiology and Immunology，Saint Louis University Medical Center，St.Louis，Missouri，USA。
6英国伦敦皇家自由医院免疫学系。
7瑞典斯德哥尔摩Karolinska Institutet医学临床微生物学系实验室医学系。
8新加坡临床科学研究所，科学，技术和研究机构（A * STAR），新加坡;新加坡国立大学研究生医学院新加坡传染病计划。电子地址：[email protected]。

抽象

使用病毒载体将外源性HBV特异性T细胞受体（TCR）引入T细胞到HBV特异性T细胞。此外，它提出了有关插入诱变和患者持续感染长寿命HBV特异性T细胞的潜在毒性的安全问题。为了开发更实用和更安全的HCC细胞治疗方法，我们使用编码抗HBV TCR的mRNA的电穿孔。 CD8 + T细胞的大约80％表达功能的HBV的TCR24小时postelectroporation，表达效率比由逆转录病毒转导得到的高得多（〜18％的特定细胞因子的产生电穿孔的T细胞的72小时期间内有效，在此之后，重新定向T细胞失去了HBV特异性功能，尽管该瞬变功能性，TCR电穿孔的T细胞可以防止肿瘤接种和抑制已建立的肿瘤的生长。在肝细胞​​癌的异种移植物模型。最后，我们建立了大型的TCR基因的方法电穿孔是产生大量高功能临床级抗HBV的T细胞，该方法表示肝癌的细胞疗法和其固有的自限制性毒性建议潜在用于其它HBV相关病状应用的实用方法。

Molecular Therapy-Nucleic Acids是由Nature Publishing Group出版的开放获取期刊。本作品采用知识共享署名 - 非商业性 - 无衍生作品3.0许可协议。要查看此许可证的副本，请访问http：// creativecommons。 Org / licenses / by-nc-nd / 3.0 /。
关键词：

TCR基因治疗;乙型肝炎病毒;肝细胞癌;

PMID：
28173945
DOI：
10.1038 / mtna.2013.43