Oncolytic Virus Therapy for Malignant Glioma

Abstract

  The replication-competent herpes simplex viruses type 1 (HSV-1) are promising therapeutic agents for malignant glioma. They can replicate in situ, spread and exhibit oncolytic activity via a direct cytocidal effect. A number of oncolytic HSV-1 viruses have been developed in recent years that have mutations in genes associated with neurovirulence and/or viral DNA synthesis to restrict viral replication to transformed cells.
  In designing recombinant viruses for clinical use, it is essential that ample safeguards be employed. G207 has deletions in both copies of the γ34.5 gene and an inactivating insertion of the Escherichia coli lacZ gene into the infected cell protein 6 (ICP6) gene. ICP6 is the large subunit of ribonucleotide reductase, a key enzyme for nucleotide metabolism and viral DNA synthesis in nondividing cells but not in dividing cells. γ34.5 is the major determinant of HSV neurovirulence. A second function of γ34.5 is to block host-cell-induced shutoff of protein synthesis in response to viral infection. This double mutation confers important features to the virus, including minimal chance of wild type reversion, preferential replication in tumor cells, attenuated neurovirulence, and ganciclovir/acyclovir hypersensitivity.
  The phase I clinical study with G207 in recurrent malignant glioma patients has shown that oncolytic HSV-1 can be safely administered into the human brain. G47Δ is the third-generation, genetically engineered HSV-1 with triple mutations that realized augmented viral replication in tumor cells, strong induction of antitumor immunity and enhanced safety in normal tissues. A clinical trial of G47Δ in patients with recurrent glioblastoma was started in 2009. One of the advantages of HSV-1 is its capacity to incorporate large and/or multiple transgenes into the viral genome. In preclinical studies, “arming” G47Δ with transgenes encoding immunomodulatory molecules, such as interleukin 12, has been shown to greatly augment the efficacy of oncolytic HSV-1 therapy.
  Oncolytic virus therapy using G47Δ can be used in combination with chemotherapy or other conventional therapies, which may in turn lead to enhanced therapeutic effects. It may serve as a useful treatment for malignant glioma that can also function as an efficient in situ tumor vaccination. We anticipate that G47Δ will soon be established as an important therapeutic modality for malignant glioma.