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CLINICAL TRIALS OF A THIRD-GENERATION RECOMBINANT ONCOLYTIC HSV-1 IN RECURRENT GLIOBLASTOMA AND OLFACTORY NEUROBLASTOMA PATIENTS

2014; Oxford University Press; Volume: 16; Issue: suppl 3 Linguagem: Inglês

10.1093/neuonc/nou209.35

1523-5866

Tomoki Todo, Mariko Tanaka, Marie Ito, Hirotaka Ito, Yasushi Ino,

Viral Infectious Diseases and Gene Expression in Insects

BACKGROUND: 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 in the viral genome of G207, a second-generation HSV-1 used in multiple clinical trials for glioblastoma in the US. In preclinical studies, G47Δ exhibited better stimulation of human antitumor immune cells, better growth properties leading to higher virus yields and increased cytopathic effect in vitro, better antitumor efficacy in various mouse cancer models, and preserved safety in HSV-1-sensitive mice compared with G207. METHODS: Clinical-grade G47Δ has been manufactured at the GMP Vector Production Facility at the Institute of Medical Science, the University of Tokyo. The first-in-man clinical trial of G47Δ started in 2009. It is an open-label, single-armed, phase I-IIa study in patients with a single lesion of recurrent glioblastoma. For each patient, G47Δ is administered stereotactically into the tumor, twice within 14 days. RESULTS: So far, the treatment has been well tolerated by patients. Clinical observations in some patients hint the efficacy of G47Δ for glioblastoma, which warrants further clinical development for glioblastoma as well as for other cancer. This first trial teaches us that conventional methods for efficacy evaluation such as RECIST and WHO criteria may not be adequate for oncolytic virus therapy. Also, a conventional dose escalation scheme for anti-cancer drugs may not be suited for designing phase I trials for oncolytic virus therapy. Because the extent of viral replication and the strength of immune responses vary considerably among patients, a preferred means of treatment using oncolytic HSV-1 may be repeating local injections until the cancer is cured. In the new clinical trial that started in 2013 for recurrent olfactory neuroblastoma, the patients receive repeated intratumoral G47Δ administration every 4 weeks until the shrinkage of the tumor or the patient is judged to have progressive disease. CONCLUSIONS: G47Δ is considered to be efficacious not only for brain tumors but for a variety of solid cancer. We aim that oncolytic virus therapy using G47Δ become a standard therapeutic option for brain tumor and cancer patients in the near future. SECONDARY CATEGORY: n/a.