A second-generation replication-conditional herpes simplex virus type 1 (HSV) vector defective for both
ribonucleotide reductase (RR) and the neurovirulence factor gamma34.5 was generated and tested for therapeutic safety and efficiency in two different experimental
brain tumor models. In culture, cytotoxic activity of this double mutant HSV vector, MGH-1, for 9L
gliosarcoma cells was similar to that of the HSV mutant, R3616, which is defective only for gamma34.5, but was significantly weaker than that of the HSV mutant hrR3, which is defective only for RR. The diminished tumoricidal effect of the gamma34.5 mutants could be accounted for by their reduced ability to replicate in 9L cells. The MGH-1 vector did not achieve significant prolongation of survival in vivo in the syngeneic 9L rat
gliosarcoma model for either single
brain tumor focus or multiple intracerebral and leptomeningeal
tumors, when the vector was applied intratumorally or intrathecally, respectively, and with or without subsequent
ganciclovir (GCV) treatment. In identical 9L
brain tumor models with single and multiple foci, application of hrR3 with or without GCV was previously shown to result in marked long-term survival. Contrary to the findings with
intrathecal injection of hrR3, no vector-related mortality was observed in any animals treated with MGH-1. Thus, in these rat
brain tumor models, the double mutant, replication-conditional HSV vector MGH-1 showed a higher therapeutic safety than the RR-minus vector, hrR3, but had clearly decreased therapeutic efficiency compared to hrR3. The development of new HSV vectors for
brain tumor gene therapy will require a balance between maximizing therapeutic efficacy and minimizing toxicity to the brain. Standardized application in
brain tumor models as presented here will help to screen new HSV vectors for these requirements.