Preferential Replication of Systemically Delivered Oncolytic Vaccinia Virus in Focally Irradiated Glioma Xenografts
Preferential Replication of Systemically Delivered Oncolytic Vaccinia Virus in Focally Irradiated Glioma Xenografts
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DOI：
10.1158/1078-0432.ccr-11-2394
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发表时间：
2012-05-01
影响因子：
11.5
通讯作者：
Szalay, Aladar A.
中科院分区：
文献类型：
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作者：
Advani, Sunil J.;Buckel, Lisa;Szalay, Aladar A.
目的：放射治疗是高级别胶质瘤治疗标准的一部分，但其结果仍然很差。将溶瘤病毒与标准的抗癌治疗相结合是一个积极的研究领域。本研究的目的是确定肿瘤靶向电离辐射(IR)如何与系统递送的溶瘤痘苗病毒相结合。实验设计：U-87胶质瘤异种移植瘤皮下或原位生长。系统注射溶瘤痘苗病毒GLV-1H68和LIVP 1.1.1，局部给予IR治疗。在双侧肿瘤模型中，在两侧种植胶质瘤异种移植瘤，系统注射溶瘤疫苗，并对右侧肿瘤进行特异性放射治疗，而左侧肿瘤则被屏蔽。结果：全身注射溶瘤疫苗病毒后，U-87移植瘤的病毒滴度明显高于未照射的移植瘤。与单一疗法相比，在皮下和原位U-87胶质瘤模型中，这种溶瘤病毒复制的增加与肿瘤异种移植消退和小鼠存活的增加相关。在双侧脑胶质瘤模型中，局部IR能够介导溶瘤疫苗的选择性复制，在该模型中，系统注射溶瘤疫苗的小鼠在照射的肿瘤中比在同一小鼠的非照射的肿瘤中优先复制。结论：这些发现表明焦点IR在增敏受照射的肿瘤部位以促进痘苗病毒介导的优先溶瘤作用具有潜在的临床作用。临床癌症资源；18(9)；2579-90。(C)2012年AACR。
Purpose: Radiotherapy is part of the standard of care in high-grade gliomas but its outcomes remain poor. Integrating oncolytic viruses with standard anticancer therapies is an area of active investigation. The aim of this study was to determine how tumor-targeted ionizing radiation (IR) could be combined with systemically delivered oncolytic vaccinia virus.Experimental Design: U-87 glioma xenografts were grown subcutaneously or orthotopically. Oncolytic vaccinia viruses GLV-1h68 and LIVP 1.1.1 were injected systemically and IR was given focally to glioma xenografts. In a bilateral tumor model, glioma xenografts were grown in both flanks, oncolytic vaccinia was injected systemically and radiation was delivered specifically to the right flank tumor, whereas the left flank tumor was shielded. Viral replication and tumor regression, after systemic injection, was analyzed and compared in irradiated and nonirradiated glioma xenografts.Results: Systemically administered oncolytic vaccinia virus replicated to higher titers in preirradiated U-87 xenografts than in nonirradiated glioma xenografts. This increased oncolytic viral replication correlated with increased tumor xenograft regression and mouse survival in subcutaneous and orthotopic U-87 glioma models compared with monotherapies. The ability of focal IR to mediate selective replication of oncolytic vaccinia was shown in a bilateral glioma model in which systemically administered oncolytic vaccinia replicated preferentially in the irradiated tumor compared with the nonirradiated tumor in the same mouse.Conclusion: These findings show a potential clinical role of focal IR in sensitizing irradiated tumor sites for preferential vaccinia virus-mediated oncolysis. Clin Cancer Res; 18(9); 2579-90. (C) 2012 AACR.