THERAPEUTIC EFFICIENCY AND SAFETY OF A 2ND-GENERATION REPLICATION-CONDITIONAL HSV1 VECTOR FOR BRAIN-TUMOR GENE-THERAPY

A second-generation replication-conditional herpes simplex virus type 1 (HSV) vector defective for both ribonucleotide reductase (RR) and th e neurovirulence factor gamma 34.5 was generated and tested for therap eutic safety and efficiency in two different experimental brain tumor models. In culture, cytotoxic activity of this double mutant HSV vecto r, MGH-1, for 9L gliosarcoma cells was similar to that of the HSV muta nt, R3616, which is defective only for gamma 34.5, but was significant ly weaker than that of the HSV mutant hrR3, which is defective only fo r RR. The diminished tumoricidal effect of the gamma 34.5 mutants coul d 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 br ain tumor focus or multiple intracerebral and leptomeningeal tumors, w hen the vector was applied intratumorally or intrathecally, respective ly, and with or without subsequent ganciclovir (GCV) treatment. In ide ntical 9L brain tumor models with single and multiple foci, applicatio n of hrR3 with or without GCV was previously shown to result in marked long-term survival. Contrary to the findings with intrathecal injecti on of hrR3, no vector-related mortality was observed in any animals tr eated with MGH-1. Thus, in these rat brain tumor models, the double mu tant, replication-conditional HSV vector MGH-1 showed a higher therape utic safety than the RR-minus vector, hrR3, but had clearly decreased therapeutic efficiency compared to hrR3. The development of new HSV ve ctors for brain tumor gene therapy will require a balance between maxi mizing therapeutic efficacy and minimizing toxicity to the brain. Stan dardized application in brain tumor models as presented here will help to screen new HSV vectors for these requirements.