Arming parvoviruses with CpG motifs to improve their oncosuppressive capacity
Arming parvoviruses with CpG motifs to improve their oncosuppressive capacity
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DOI：
10.1002/ijc.23472
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发表时间：
2008-06-15
影响因子：
6.4
通讯作者：
Rommelaere, Jean
中科院分区：
文献类型：
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作者：
Raykov, Zahari;Grekova, Svetlana;Rommelaere, Jean
溶瘤病毒代表了癌症治疗的新工具。除了特异性杀死癌细胞（溶瘤）外，这些药物还提供危险信号，促使免疫系统消除病毒感染的肿瘤。作为溶瘤事件的结果，先天和适应性免疫系统获得肿瘤抗原，这导致交叉启动和疫苗接种效果。这里的目的是看看我们是否可以通过将免疫刺激CpG基序结合到溶瘤性细小病毒（H-1PV）的单链基因组中来增强这种辅助能力。我们设计了2个富含cpg的H-1PV变体（JabCG1和JabCG2），同时保留了亲本病毒的复制能力和溶瘤特性。随着CpG含量的增加，JabCG1和JabCG2基因组在体外被证明比野生型H-1PV DNA更有效地触发tlr -9介导的信号传导。在MH3924A肝癌肺转移大鼠模型中评估了抗肿瘤活性，其中亲本病毒或修饰病毒感染作为皮下给药的自体细胞疫苗的体外佐剂。在排除对转移瘤的直接溶瘤作用的情况下，JabCG2载体显示出增强的免疫原性，在纵隔（肿瘤引流）淋巴结中诱导细胞免疫标记（IFN γ）和树突状细胞激活（CD80, CD86）。与其他疫苗接种计划（H-1PV-、JabCG1-、JabGC-或模拟处理的细胞）相比，这导致转移率显著降低（50%）。这些数据提供了原理证明，增加溶瘤病毒中免疫刺激CpG基序的数量，可以通过诱导抗肿瘤疫苗接种来提高其整体抗癌效果。(C) 2008 Wiley-Liss, Inc。
Oncolytic viruses represent novel tools for cancer treatment. Besides specifically killing cancer cells (oncolysis), these agents also provide danger signals, prompting the immune system to eliminate virus-infected tumours. As a consequence of oncolytic events, the innate and adaptive immune systems gain access to tumour antigens, which result in cross-priming and vaccination effects. Here the aim was to see whether we could enhance this adjuvant capacity by incorporating immunostimulatory CpG motifs into the single-stranded genome of an oncolytic parvovirus (H-1PV). We engineered 2 CpG-enriched H-1PV variants (JabCG1 and JabCG2), preserving both the replication competence and the oncolytic features of the parental virus. In keeping with their increased CpG content, the JabCG1 and JabCG2 genomes proved in vitro to be more potent triggers of TLR-9-mediated signalling than wild-type H-1PV DNA. Antitumour activity was evaluated in a rat model of MH3924A hepatoma lung metastases, where an infection with parental or modified viruses served as an ex vivo adjuvant to a subcutaneously administered autologous cell vaccine. In this setup, which excludes direct oncolytic effects on metastases, the JabCG2 vector displayed enhanced immunogenicity, inducing markers of cellular immunity (IFN gamma) and dendritic cell activation (CD80, CD86) in mediastinal (tumour-draining) lymph nodes. This led to a significantly reduced metastatic rate (50%) as compared to other vaccination schedules (H-1PV-, JabCG1-, JabGC- or mock-treated cells). The data provide proof of principle that increasing the number of immunostimulatory CpG motifs within oncolytic viruses makes it possible to improve their overall anticancer effect by inducing antitumour vaccination. (C) 2008 Wiley-Liss, Inc.