Toxicity and Efficacy of a Novel GADD34-expressing Oncolytic HSV-1 for the Treatment of Experimental Glioblastoma

Abstract

<b>Purpose:</b> Glioblastoma (GBM) is the most common primary central nervous system cancer in adults. Oncolytic HSV-1 (oHSV) is the first FDA-approved gene therapy approach for the treatment of malignant melanoma. For GBM, oHSVs need to be engineered to replicate within and be toxic to the glial tumor but not to normal brain parenchymal cells. We have thus engineered a novel oHSV to achieve these objectives.<b>Experimental Design:</b> NG34 is an attenuated HSV-1 with deletions in the genes encoding viral ICP6 and ICP34.5. These mutations suppress virus replication in nondividing brain neurons. NG34 expresses the human <i>GADD34</i> gene under transcriptional control of a cellular Nestin gene promoter/enhancer element, whose expression occurs selectively in GBM. <i>In vitro</i> cytotoxicity assay and survival studies with mouse models were performed to evaluate therapeutic potency of NG34 against glioblastoma. <i>In vivo</i> neurotoxicity evaluation of NG34 was tested by intracerebral inoculation.<b>Results:</b> NG34 replicates in GBM cells <i>in vitro</i> with similar kinetics as those exhibited by an oHSV that is currently in clinical trials (rQNestin34.5). Dose-response cytotoxicity of NG34 in human GBM panels was equivalent to or improved compared with rQNestin34.5. The <i>in vivo</i> efficacy of NG34 against two human orthotopic GBM models in athymic mice was similar to that of rQNestin34.5, whereas intracerebral injection of NG34 in the brains of immunocompetent and athymic mice showed significantly better tolerability. NG34 was also effective in a syngeneic mouse glioblastoma model.<b>Conclusions:</b> A novel oHSV encoding <i>GADD34</i> is efficacious and relatively nontoxic in mouse models of GBM. <i>Clin Cancer Res; 24(11); 2574-84. ©2018 AACR</i>.