The Oncolytic Virus G47Δ Shows Efficacy and Safety in Glioblastoma

Prognosis of patients with glioblastoma remains poor, and recurrence after standard-of-care therapy is frequent. As nonconventional therapeutic approaches are needed, a third-generation oncolytic herpes simplex virus type 1 (HSV-1) has been constructed, termed G47Δ, which has deletion of the α47 gene as well as deletion in the γ34.5 gene and ICP6 inactivation. Use of this virus has demonstrated tumor-specific replication and was shown to be safe in a first-in-human trial of recurrent glioblastoma. To test the efficacy of G47Δ in patients with residual or recurrent glioblastoma, Todo and colleagues conducted a single-arm, phase II clinical trial in 19 adult patients in whom G47Δ was surgically administered repeatedly for up to six doses. The primary endpoint of this study was the 1-year survival rate, with secondary endpoints of overall survival (OS) and progression-free survival (PFS), all of which were after G47Δ initiation. The primary endpoint was met with the 1-year survival rate being 84.2%. Median OS and median PFS were 20.2 and 4.7 months, respectively. Post hoc analysis of IDH1 status showed mutation in six of the 19 patients, with OS not being affected by IDH1 status. Moreover, MGMT methylation was available for five patients, and MGMT expression analysis post hoc indicated no effect on median OS. Assessment of best overall response showed a partial response in one patient, with stable disease observed in 18 patients. Evaluation of safety showed that 100% of patients experienced treatment-related adverse events, with a majority including fever, vomiting, nausea, and reduction in lymphocyte count. G47Δ-related adverse events grade 3 or higher were observed in seven patients (36.8%), including five patients with reduced lymphocyte count that recovered without treatment. Viral shedding was an exploratory endpoint and was not observed in any patient after day 0. Overall, this trial demonstrates safety and efficacy in the use of G47Δ in patients with residual or recurrent glioblastoma leading to its approval in Japan and suggests the potential expansion of indications for G47Δ to other solid tumors.

Todo T, Ito H, Ino Y, Ohtsu H, Ota Y, Shibahara J, et al. Intratumoral oncolytic herpes virus G47Δ for residual or recurrent glioblastoma: a phase 2 trial. Nat Med 2022 Jul 21 [Epub ahead of print].

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