Experimental Therapy for Malignant Brain Tumors Using Genetically Engineered Herpes Simplex Virus Type 1

Abstract

We are exploring a novel experimental treatment for malignant brain tumors utilizing a genetically engineered, attenuated, replication-competent herpes simplex virus type 1 (HSV-1). Our previous studies demonstrated that a thymidine kinase-deficient HSV-1 mutant (dlsptk) could destroy human glioma cells in an animal brain tumor model. This HSV-1 mutant has a 360-base pair deletion in the thymidine kinase gene, allowing for replication in dividing tumor cells but not in nondividing cells. We hypothesized that such HSV-1 mutants might replicate in actively growing tumor cells and effectively kill malignant brain tumors while sparing normal brain cells. So that this therapy could become an effective clinical choice, we have examined different HSV-1 mutants. We tested a ribonucleotide reductase-deficient mutant as an experimental treatment for malignant brain tumors. The HSV-1 mutant hrR3, containing Escherichia coli lacZ gene in the ICP6 gene that encodes the large subunit of ribonucleotide reductase, is hypersensitive to antiherpetic agents acyclovir and ganciclovir while dlsptk is resistant. We have demonstrated that hrR3 destroyed human glioblastoma cells in vitro and in vivo as well as dlsptk. These results have stimulated interest in the possible clinical trial of hrR3 for the treatment of malignant brain tumors.