Enhanced oncolytic potency of vesicular stomatitis virus through vector-mediated inhibition of NK and NKT cells.
Enhanced oncolytic potency of vesicular stomatitis virus through vector-mediated inhibition of NK and NKT cells.
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DOI：
10.1038/cgt.2008.74
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发表时间：
2009-03
影响因子：
6.4
通讯作者：
中科院分区：
文献类型：
--
作者：
重组溶瘤病毒是治疗恶性癌症的一种有希望的替代选择。我们之前报道了重组水泡性口炎病毒（VSV）载体在肝细胞癌（HCC）大鼠模型中的安全性和有效性。然而，VSV治疗的全部潜力受到病毒给药后早期观察到的瘤内病毒复制突然下降的限制，这一现象与感染病变内炎症细胞的积累相吻合。为了克服这些细胞的抗病毒功能，我们提出了一种重组病毒rVSV-UL141，它表达一种来自人巨细胞病毒的蛋白，已知该蛋白下调NK细胞活化配体CD155。修饰后的载体在体外抑制NK细胞募集，并在体内降低NK和NKT细胞在肿瘤内的积聚。通过肝动脉输注rVSV- ul141，在患有原位多灶性HCC的免疫能力强的Buffalo大鼠中，肿瘤内病毒复制比对照rVSV载体增加了1倍，这意味着肿瘤坏死增强，生存期大幅延长。此外，这些结果是在没有明显毒性的情况下取得的。目前的研究表明，这一策略适用于开发有效和安全的溶瘤药物来治疗多灶性HCC，以及未来潜在的多种其他癌症。
Recombinant oncolytic viruses represent a promising alternative option for the treatment of malignant cancers. We have previously reported the safety and efficacy of recombinant vesicular stomatitis virus (VSV) vectors in a rat model of hepatocellular carcinoma (HCC). However, the full potential of VSV therapy is limited by a sudden decline in intratumoral virus replication observed early after viral administration, a phenomenon which coincides with an accumulation of inflammatory cells within infected lesions. To overcome the anti-viral function of these cells, we present a recombinant virus, rVSV-UL141, which expresses a protein from human cytomegalovirus known to downregulate the NK cell-activating ligand CD155. The modified vector resulted in an inhibition of NK cell recruitment in vitro, as well as decreased intra-tumoral accumulations of NK and NKT cells in vivo. Administration of rVSV-UL141 via hepatic artery infusion in immune-competent Buffalo rats harboring orthotopic, multifocal HCC lesions, resulted in a one-log elevation of intratumoral virus replication over a control rVSV vector, which translated to enhanced tumor necrosis and substantial prolongation of survival. Moreover, these results were achieved in the absence of apparent toxicities. The present study suggests the applicability of this strategy for the development of effective and safe oncolytic agents to treat multi-focal HCC, and potentially a multitude of other cancers, in the future.
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DOI：
10.1073/pnas.92.10.4477
发表时间：
1995-05-09
影响因子：
11.1
作者：
LAWSON, ND;STILLMAN, EA;ROSE, JK
通讯作者：
ROSE, JK
影响因子：
11.2
作者：
Ebert, O;Shinozaki, K;Woo, SLC
通讯作者：
Woo, SLC
影响因子：
56.9
作者：
Murray, CJL;Lopez, AD
通讯作者：
Lopez, AD
影响因子：
4.8
作者：
Baraz, L;Khazanov, E;Nagler, A
通讯作者：
Nagler, A
影响因子：
11.4
作者：
Bryant, NA;Davis-Poynter, N;Alcami, A
通讯作者：
Alcami, A