Cyclophosphamide facilitates antitumor efficacy against subcutaneous tumors following intravenous delivery of reovirus
Cyclophosphamide facilitates antitumor efficacy against subcutaneous tumors following intravenous delivery of reovirus
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DOI：
10.1158/1078-0432.ccr-07-1510
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发表时间：
2008-01-01
影响因子：
11.5
通讯作者：
Harrington, Kevin
中科院分区：
文献类型：
--
作者：
Qiao, Jian;Wang, Hongxun;Harrington, Kevin
目的：本研究的目的是研究是否有可能在免疫活性宿主中实现溶瘤呼肠孤病毒的真正全身递送，使用环磷酰胺克服有效肿瘤内递送和静脉内复制的一些障碍。实验设计：将呼肠孤病毒的I. v.递送与不同的腹膜内施用环磷酰胺的方案组合在具有建立的s.c. B16肿瘤肿瘤内病毒复制、肿瘤大小和存活率与血液中的中和抗体（NAb）水平一起进行沿着测量。最后，差分毒性的病毒/环磷酰胺方案进行了监测，通过病毒复制在全身器官，生存，和心脏damage.Results：重复静脉注射呼肠孤病毒是有效的播种瘤内病毒复制/溶瘤。然而，通过静脉注射病毒与环磷酰胺联合，从消退的肿瘤中回收的病毒滴度为10（7）至10（8）个空斑形成单位/mg。消除NAb的环磷酰胺剂量与严重毒性相关，其特征在于全身器官中的病毒复制-毒性通过重复将呼肠孤病毒注射到B细胞敲除小鼠中来反映。接下来，我们重新调整了环磷酰胺和静脉注射病毒的剂量，使得在呼肠孤病毒注射前24小时给予3 mg环磷酰胺的剂量，并且每6天重复一次该方案。使用该方案，高水平的肿瘤内病毒进入和复制（类似于10（7）空斑形成单位/毫克肿瘤）保持沿着NAb的全身保护水平，并且仅具有非常轻微的非危及生命的毒性。一方面，它们阻碍病毒的重复施用，但另一方面，它们提供了重要的安全机制，通过该机制，从剧烈的肿瘤内复制释放的病毒在其扩散和引起毒性之前被中和。这些数据支持在开发溶瘤病毒全身给药的仔细对照临床试验中使用环磷酰胺调节而非消融患者NAb。
Purpose: The purpose of the present study was to investigate whether it is possible to achieve truly systemic delivery of oncolytic reovirus, in immunocompetent hosts, using cyclophosphamide to overcome some of the barriers to effective intratumoral delivery and replication of i.v.. injected virus.Experimental Design: I.v. delivery of reovirus was combined with different regimens of i.p. administered cyclophosphamide in C57BI/6 mice bearing established s.c. B16 tumors. Intratumoral viral replication, tumor size, and survival were measured along with levels of neutralizing antibody (NAb) in the blood. Finally, differential toxicities of the virus/cyclophosphamide regimens were monitored through viral replication in systemic organs, survival, and cardiac damage.Results: Repeated i.v. injection of reovirus was poorly effective at seeding intratumoral viral replication/oncolysis. However, by combining i.v. virus with cyclophosphamide, viral titers of between 10(7) and 10(8) plaque-forming units per milligram were recovered from regressing tumors. Doses of cyclophosphamide that ablated NAb were associated with severe toxicities, characterized by viral replication in systemic organs-toxicities that are mirrored by repeated reovirus injections into B-cell knockout mice. Next, we restructured the dosing of cyclophosphamide and i.v. virus such that a dose of 3 mg cyclophosphamide was administered 24 h before reovirus injection, and this schedule was repeated every 6 days. Using this protocol, high levels of intratumoral viral access and replication (similar to 10(7) plaque-forming units per milligram tumor) were maintained along with systemically protective levels of NAb and only very mild, non - life-threatening toxicity.Conclusion: NAb to oncolytic viruses play a dual role in the context of systemic viral delivery; on one hand, they hinder repeated administration of virus but on the other, they provide an important safety mechanism by which virus released from vigorous intratumoral replication is neutralized before it can disseminate and cause toxicity. These data support the use of cyclophosphamide to modulate, but not ablate, patient NAb, in development of carefully controlled clinical trials of the systemic administration of oncolytic viruses.