Genetically engineered, conditionally replicating herpes simplex viruses type 1 (HSV-1) are promising therapeutic agents for cancer. We have developed a triple-mutated, third-generation oncolytic HSV-1, G47Δ, by introducing an additional genetic mutation to the viral genome of G207, a second generation HSV-1, used in clinical trials for malignant glioma in the United States. Preclinical studies demonstrated that G47Δ exhibited increased antitumor efficacy in various tumor models while preserving the safety of G207. Prior to the first-in-man clinical trial, G47Δ genome structure analysis, stability tests, and preclinical safety evaluation using HSV-1-susceptible A/J mice were performed. After development and optimization of manufacturing processes, clinical-grade G47Δ was produced at the GMP vector production facility of the University of Tokyo. Quality tests under GLP were completed for clinical products at 4 manufacturing steps. The first clinical trial of G47Δ is designed as an open labeled, single armed, phase I-II study for patients with recurrent glioblastoma. Patients with a single lesion, age 18 or older, and with Karnofsky Performance Scale (KPS) 70% or higher are enrolled. G47Δ is administered stereotactically into multiple sites of the tumor, twice within 14 days. The primary endpoint is to assess the safety of G47Δ, and the secondary endpoint is to assess the efficacy by tumor size and progression-free survival. After 3 years of contact with and review by regulatory authorities, the final governmental approval was obtained in May 2009, and the patient registration began in November 2009. In this paper, we also review the background of the clinical development of G47Δ.
