Malignant gliomas have defied advances in traditional therapies and have engendered intensive exploration into the study of novel treatment modalities, including the use of viral vectors for gene therapy. Mutation of the gamma134.5 gene in HSV-1 has made it a promising therapeutic candidate as a conditionally replicating viral vector whose successful replication and oncolysis is limited to tumor cells. The proposed studies will improve the potential of HSV as a gene therapy agent by both enhancing its intrinsic anti-tumor capabilities and optimizing its extrinsic arsenal of recombinant immunostimulatory therapeutic genes. The first approach will be to enhance its """"""""intrinsic"""""""" ability to function within the tumor environment. Serially passaging gamma134.5-deficient HSVs through human malignant gliomas (D54 and U87) grown in the flanks of SCID mice will allow in vivo selective pressures to produce mutants possessing enhanced anti-glioma activity. The second """"""""extrinsic"""""""" approach will augment the cytoreductive and curative ability of the virus by optimizing its ability to promote tumor-targeted immune responses. Construction of an HSV-1 vector expressing IL-18 is expected to elicit increased immune cell infiltrates targeting tumor cells for destruction. Furthermore, using a combination of IL- 18-expressing HSV with M002 (IL-12-expressing HSV), or an HSV expressing both IL-12 & IL-18, should lead to greater anti-tumor effects due to the proven synergy between IL-12 and IL-18. Finally, we anticipate that unifaction of oncolytics gamma134.5(-) HSV-1 vectors selected through serial passaging with different immunostimulatory genes will deliver a therapeutic """"""""double hit"""""""" against these recalcitrant and nearly universally fatal malignant gliomas. ? ? ?
| Shah, Amish C; Parker, Jacqueline N; Shimamura, Masako et al. (2009) Spontaneous and Engineered Compensatory HSV Mutants that Counteract the Host Antiviral PKR Response. Viruses 1:510-22 |
| Shah, A C; Parker, J N; Gillespie, G Y et al. (2007) Enhanced antiglioma activity of chimeric HCMV/HSV-1 oncolytic viruses. Gene Ther 14:1045-54 |
| Shah, Amish C; Price, Kathleen H; Parker, Jacqueline N et al. (2006) Serial passage through human glioma xenografts selects for a Deltagamma134.5 herpes simplex virus type 1 mutant that exhibits decreased neurotoxicity and prolongs survival of mice with experimental brain tumors. J Virol 80:7308-15 |
