MUTANT HERPES-SIMPLEX VIRUS-INDUCED REGRESSION OF TUMORS GROWING IN IMMUNOCOMPETENT RATS

Herpes simplex virus (HSV) mutants kill dividing tumor cells but spare non-proliferating, healthy brain tissue and may be useful in developi ng new treatment strategies for malignant brain tumors. Two HSV mutant s, a thymidine kinase deficient virus (TK-) and a ribonucleotide reduc tase mutant (RR-), killed 7/7 human tumor cell lines in tissue culture . The TK- HSV killed Rat RG2 glioma and W256 carcinoma lines but not t he rat C6 glioma in culture. TK- HSV replication (12 pfu/cell) was sim ilar to wild-type HSV (10 pfu/cell) in rapidly dividing W256 cells in tissue culture, but was minimal (< 1 pfu/cell) in serum-starved cells, suggesting that the proliferative activity of tumor cells at the site and time of TK- HSV injection may influence efficacy in vivo. Subcuta neous W256 tumors in male Sprague-Dawley rats were injected with TK- H SV or virus free inoculum. A significant effect of TK- HSV therapy on W256 tumor growth was demonstrated compared to controls (p = 0.002). C omplete regression was observed in 4/9 experimental tumors, with no re currence over 6 months. Tumor growth in the remaining 5/9 animals was attenuated during the first 3 to 5 days after treatment, but not beyon d 5 days compared to 9 matched control animals; no tumor regression wa s observed in any of the control animals. These results suggest that H SV mutants are potentially useful as novel therapeutic agents in the t reatment of tumors in immunocompetent subjects.