利用一种新的转录和翻译双调控的溶瘤性单纯疱疹病毒1型靶向表达癌胚抗原的肿瘤。

IF 5.3 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Dmitry V Chouljenko, Yanal M Murad, I-Fang Lee, Zahid Delwar, Jun Ding, Guoyu Liu, Xiaohu Liu, Xuexian Bu, Yi Sun, Ismael Samudio, William Wei-Guo Jia
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引用次数: 2

摘要

VG2025是一种重组溶瘤性单纯疱疹病毒1型(HSV-1),它利用关键病毒基因的转录和翻译双重调控(TTDR)来增强病毒安全性,促进肿瘤特异性病毒复制,但不降低毒力。TTDR平台基于使用肿瘤特异性癌胚抗原(CEA)启动子转录控制必需的HSV-1即时早期蛋白ICP27,以及使用多个microRNA (miR)结合位点翻译控制神经毒力因子ICP34.5。VG2025进一步加入IL-12和IL-15/IL-15受体α亚基复合物,以增强溶瘤性单纯疱疹病毒的抗肿瘤和免疫刺激特性。体外验证了TTDR策略并显示出高选择性。在肿瘤内和静脉给药后观察到很强的体内抗肿瘤疗效。明确的体外和免疫记忆效应也很明显,表明有强大的抗肿瘤免疫反应。与骨干病毒相比,治疗肿瘤的基因表达谱显示免疫细胞浸润和多种免疫信号通路的激活增加。在小鼠和恒河猴中证实了无神经毒性。综上所述,增强的肿瘤清除率、良好的安全性以及CEA水平与病毒复制效率之间的正相关性可能为基于生物标志物的精准医学在溶瘤病毒治疗中的应用提供了机会。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Targeting carcinoembryonic antigen-expressing tumors using a novel transcriptional and translational dual-regulated oncolytic herpes simplex virus type 1.

Targeting carcinoembryonic antigen-expressing tumors using a novel transcriptional and translational dual-regulated oncolytic herpes simplex virus type 1.

Targeting carcinoembryonic antigen-expressing tumors using a novel transcriptional and translational dual-regulated oncolytic herpes simplex virus type 1.

Targeting carcinoembryonic antigen-expressing tumors using a novel transcriptional and translational dual-regulated oncolytic herpes simplex virus type 1.

VG2025 is a recombinant oncolytic herpes simplex virus type 1 (HSV-1) that uses transcriptional and translational dual regulation (TTDR) of critical viral genes to enhance virus safety and promote tumor-specific virus replication without reducing virulence. The TTDR platform is based on transcriptional control of the essential HSV-1 immediate-early protein ICP27 using a tumor-specific carcinoembryonic antigen (CEA) promoter, coupled with translational control of the neurovirulence factor ICP34.5 using multiple microRNA (miR)-binding sites. VG2025 further incorporates IL-12 and the IL-15/IL-15 receptor alpha subunit complex to enhance the antitumor and immune stimulatory properties of oncolytic HSVs. The TTDR strategy was verified in vitro and shown to be highly selective. Strong in vivo antitumor efficacy was observed following both intratumoral and intravenous administration. Clear abscopal and immune memory effects were also evident, indicating a robust antitumor immune response. Gene expression profiling of treated tumors revealed increased immune cell infiltration and activation of multiple immune-signaling pathways when compared with the backbone virus. Absence of neurotoxicity was verified in mice and in rhesus monkeys. Taken together, the enhanced tumor clearance, excellent safety profile, and positive correlation between CEA levels and viral replication efficiency may provide an opportunity for using biomarker-based precision medicine in oncolytic virotherapy.

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来源期刊
Molecular Therapy Oncolytics
Molecular Therapy Oncolytics Medicine-Oncology
CiteScore
10.90
自引率
3.50%
发文量
152
审稿时长
6 weeks
期刊介绍: Molecular Therapy — Oncolytics is an international, online-only, open access journal focusing on the development and clinical testing of viral, cellular, and other biological therapies targeting cancer.
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