Cancer Therapy: Preclinical Preferential Replication of Systemically Delivered Oncolytic Vaccinia Virus in Focally Irradiated Glioma Xenografts

Purpose:Radiotherapy is part of the standardof care inhigh-grade gliomasbut its outcomes remainpoor. 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 tumormodel, 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 U87 xenografts than in nonirradiated glioma xenografts. This increased oncolytic viral replication correlated with increased tumor xenograft regression andmouse 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 comparedwith the nonirradiated tumor in the samemouse. 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. 2012 AACR.