282. Antitumor Efficacy of Intravenous Administration of Oncolytic Herpes Simplex Virus Expressing Interleukin 12
Authors: Yi Guan, Yasushi Ino, Hiroshi Fukuhara, Tomoki Todo
Journal: Molecular Therapy (2006)

Object: Genetically-engineered oncolytic herpes simplex viruses type 1 (HSV-1) vectors are effective therapeutic reagents for cancer. The most common route of delivery so far has been a direct intratumoral inoculation, but an intravenous delivery would further broaden the clinical application of oncolytic HSV-1 vectors if proven effective. The purpose of this study was to test whether expression of interleukin 12 (IL-12) by oncolytic HSV-1 vectors improves the antitumor efficacy when delivered intravenously in mice bearing established tumors.Methods: A third-generation HSV-1 (T-01) was newly created from G47D. T-01 has triple deletions in the g34.5, ICP6 and a47 genes, and efficiently replicates in and kills cancer cells without harming normal tissues. T-mfIL12 was created by inserting the fusion-type murine IL-12 gene into the deleted ICP6 region of T-01. HSV-1-susceptible A/J mice and syngeneic, poorly-immunogenic Neuro2a (neuroblastoma) cells were used for in vivo evaluation. Mock, T-01 or T-mfIL12 (5 × 106 pfu) was injected into the tail vein three times (days 0, 2, 4) in mice bearing subcutaneous, intracerebral or intravenously disseminated tumors.Results: We observed that intravenous delivery of T-01 and T- mfIL12 both caused a significant inhibition of tumor growth compared with mock treatment in mice bearing subcutaneous tumors. T-mfIL12 was significantly more efficacious than T-01. In mice bearing intracerebral tumors, intravenous delivery of T-mfIL12 prolonged the survival (Mock vs. T-mfIL12, p<0.05), although not statistically significant versus T-01 treatments. Similar results were observed when evaluated in mice injected intravenously with Neuro2a cells to mimic systemic metastases. There was no apparent systemic or neurological toxicity observed with the treatment regimen used. Conclusion: Intravenous delivery of oncolytic HSV-1 vectors was effective in controlling the tumor growth, and the efficacy could be improved by "arming" the vectors with functional transgenes such as IL-12. Intravenous administration of IL-12-expressing oncolytic HSV-1 vectors showed no apparent side effects at the doses tested. Further optimization of therapeutic designs may make intravenous delivery a useful strategy for treating primary solid tumors as well as metastases. Object: Genetically-engineered oncolytic herpes simplex viruses type 1 (HSV-1) vectors are effective therapeutic reagents for cancer. The most common route of delivery so far has been a direct intratumoral inoculation, but an intravenous delivery would further broaden the clinical application of oncolytic HSV-1 vectors if proven effective. The purpose of this study was to test whether expression of interleukin 12 (IL-12) by oncolytic HSV-1 vectors improves the antitumor efficacy when delivered intravenously in mice bearing established tumors. Methods: A third-generation HSV-1 (T-01) was newly created from G47D. T-01 has triple deletions in the g34.5, ICP6 and a47 genes, and efficiently replicates in and kills cancer cells without harming normal tissues. T-mfIL12 was created by inserting the fusion-type murine IL-12 gene into the deleted ICP6 region of T-01. HSV-1-susceptible A/J mice and syngeneic, poorly-immunogenic Neuro2a (neuroblastoma) cells were used for in vivo evaluation. Mock, T-01 or T-mfIL12 (5 × 106 pfu) was injected into the tail vein three times (days 0, 2, 4) in mice bearing subcutaneous, intracerebral or intravenously disseminated tumors. Results: We observed that intravenous delivery of T-01 and T- mfIL12 both caused a significant inhibition of tumor growth compared with mock treatment in mice bearing subcutaneous tumors. T-mfIL12 was significantly more efficacious than T-01. In mice bearing intracerebral tumors, intravenous delivery of T-mfIL12 prolonged the survival (Mock vs. T-mfIL12, p<0.05), although not statistically significant versus T-01 treatments. Similar results were observed when evaluated in mice injected intravenously with Neuro2a cells to mimic systemic metastases. There was no apparent systemic or neurological toxicity observed with the treatment regimen used. Conclusion: Intravenous delivery of oncolytic HSV-1 vectors was effective in controlling the tumor growth, and the efficacy could be improved by "arming" the vectors with functional transgenes such as IL-12. Intravenous administration of IL-12-expressing oncolytic HSV-1 vectors showed no apparent side effects at the doses tested. Further optimization of therapeutic designs may make intravenous delivery a useful strategy for treating primary solid tumors as well as metastases.