TOXICITY STUDIES IN THYMIDINE KINASE-DEFICIENT HERPES-SIMPLEX VIRUS THERAPY FOR MALIGNANT ASTROCYTOMA

Previous studies have shown that genetically engineered thymidine kina se (tk)-defective herpes simplex virus type 1 (HSV-1) can effectively and selectively destroy gliomas in animal models. The consequences of viral infection and tumor regression must be characterized before this therapy can be applied in human trials. To study the potential for lo ng-term toxicity, immunocompetent rats harboring 9L gliosarcomas were injected intratumorally with a tk-defective HSV-I, KOS-SB, at titers t hat previously have been demonstrated to cause tumor regression. In an imals surviving 3 months or longer following viral treatment, there wa s no evidence of persistent infection or inflammation in peritumoral b rain tissue or in remote systemic organs studied with routine histolog ical and immunocytochemical analyses. Polymerase chain reaction using primers specific for HSV-1 detected HSV-1 DNA in peritumoral tissue on ly in animals sacrificed within 3 months of viral injection. There was no evidence of HSV-1 DNA in systemic tissues at any time after treatm ent. We conclude that stereotactic intratumoral injection of tk-defici ent HSV can be attempted for the treatment of brain tumors without ris k of systemic infection or significant toxicity to normal brain or rem ote proliferating tissues.