Experimental Viral Therapy for the Treatment of Malignant Glioma Using Recombinant Herpes Simplex Virus Type 1

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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 previos studies demonstrated that a thymidine kinase-deficient HSV-1 mutant(dlsptk), could destroy human glioma cells, allowing for replication in dividing tumor cells but not in non-dividing 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. In order for this therapy to become an effective clinical choice, we have created a multiple deletion mutant of herpes simple virus type 1 which has favorable properties for the treatment of human malignant brain tumors. This mutant, termed G207, has 1.0 kb deletions at both gamma34.5 loci and a lacZ gene insertion inactivating the ICP6 locus. G207 causes a spreading infection killing human glioma cells in monolayr cultures. In nude mice harboring subcutaneous or intracerebral U-87MG gliomas, intraneoplastic inoculation of G207 causes decreased tumor growth and/or prolonged survival. G207 is avirulent upon intracerebral inoculation of mice and HSV sensitive non-human primates. These results have stimulated interest in its possible clinical trial for the treatment of malignant brain tumors.