Immunosuppression enhances oncolytic adenovirus replication and antitumor efficacy in the Syrian hamster model.
Immunosuppression enhances oncolytic adenovirus replication and antitumor efficacy in the Syrian hamster model.
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DOI：
10.1038/mt.2008.162
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发表时间：
2008-10
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影响因子：
--
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中科院分区：
文献类型：
--
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我们最近描述了一种免疫活性的溶瘤腺病毒（Ads）的叙利亚仓鼠模型，该模型允许病毒在肿瘤细胞以及一些正常组织中复制。该模型允许探索病毒、肿瘤、正常器官和宿主免疫系统之间的相互作用，这些相互作用不能在先前用于溶瘤Ad领域的免疫缺陷或非允许动物模型中进行检查。在此，我们询问对溶瘤Ad的免疫应答是否增强或限制抗肿瘤功效。我们首先确定，环磷酰胺（CP）是一种有效的免疫抑制剂在叙利亚仓鼠和CP单独对肿瘤生长没有影响。重要的是，我们发现溶瘤性广告的抗肿瘤功效在免疫抑制动物中显著增强。在接受病毒治疗加免疫抑制的动物中，观察到肿瘤组织学的显著差异，并且在许多情况下几乎没有存活的肿瘤。值得注意的是，我们还确定免疫抑制允许肿瘤内病毒水平长时间保持升高。尽管在免疫活性动物中可以实现有利的肿瘤应答，但从肿瘤中清除病毒的速率可能导致不同的抗肿瘤功效。因此，免疫抑制允许持续的Ad复制和溶瘤，这导致对肿瘤生长的抑制显著改善。
We recently described an immunocompetent Syrian hamster model for oncolytic adenoviruses (Ads) that permits virus replication in tumor cells as well as some normal tissues. This model allows exploration of interactions between the virus, tumor, normal organs, and host immune system that could not be examined in the immunodeficient or nonpermissive animal models previously used in the oncolytic Ad field. Here we asked whether the immune response to oncolytic Ad enhances or limits antitumor efficacy. We first determined that cyclophosphamide (CP) is a potent immunosuppressive agent in the Syrian hamster and that CP alone had no effect on tumor growth. Importantly, we found that the antitumor efficacy of oncolytic Ads was significantly enhanced in immunosuppressed animals. In animals that received virus therapy plus immunosuppression, significant differences were observed in tumor histology, and in many cases little viable tumor remained. Notably, we also determined that immunosuppression allowed intratumoral virus levels to remain elevated for prolonged periods. Although favorable tumor responses can be achieved in immunocompetent animals, the rate of virus clearance from the tumor may lead to varied antitumor efficacy. Immunosuppression, therefore, allows sustained Ad replication and oncolysis, which leads to substantially improved suppression of tumor growth.
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