*2.2. G207*

G207 is an attenuated HSV-1 variant that contains an insertion of the *Escherichia coli lac*Z sequence in the *ICP6* gene and deletions at both γ34.5 loci [23], aiming at diminishing viral growth and neurovirulence [14,15]. Deletion of the ribonucleotide reductase encoding *ICP6* gene allows for selective viral replication in dividing (tumor) cells [23]. Markert and colleagues tested the safety of G207 in several phase I studies in recurrent or residual anaplastic astrocytoma, glioblastoma, and gliosarcoma. The initial phase I study [24] evaluated the safety profile of intratumorally inoculated G207 in a dose-escalation scheme. While it was demonstrated that the virus could be safely administered without the development of encephalitis, other potential adverse events (AEs) were difficult to distinguish from disease-related symptoms. MRI (magnetic resonance imaging) confirmed a decrease in enhancement volume in 40% of the patients; two patients tested positive for the HSV-1 and lacZ sequence in the tissue analysis, suggesting successful inoculation of G207. A follow-up phase Ib study investigated the safety profile of two inoculations each before and after tumor resection in patients with recurrent glioblastoma [25]. Again, no signs of encephalitis were detected and the therapy was well tolerated. Every patient experienced at least one AE with 13% being possibly associated with G207, but an ameliorated Karnofsky Performance Score (KPS) was noticed in 50% of the patients. Another subsequent phase I study focused on the combination of G207 with radiation in patients with recurrent or residual anaplastic astrocytoma, glioblastoma, and gliosarcoma [26]. Patients were treated with G207 via stereotactic inoculation and subsequent radiation with 5 Gy. As in the other two studies, no patient developed encephalitis; in some cases, seizures were classified as possible G207-related adverse events. Overall,

the treatment combination was assessed as safe. The secondary endpoint of this study was efficacy: The median progression-free survival was stated with 2.5 months, the median survival from G207 inoculation added up to 7.5 months. Signs of therapy response in MRI were noticed in two patients on three occasions.
