*2.1. HSV-1716*

HSV-1716 (Seprehvir by Virttu Biologics/Sorrento Therapeutics Inc. San Diego, CA, USA) has deletions of both copies of γ*34.5*/*RL1* that mitigate neurovirulence [15]. This variant has been tested for the treatment of recurrent malignant glioma [21] and stage IV melanoma [22] in phase I studies. Toxicity was the primary endpoint in both studies. Rampling et al. injected HSV-1716 stereotactically into the tumor of patients with recurrent anaplastic astrocytoma and glioblastoma. No encephalitis or virus shedding could be detected, thereby demonstrating safe delivery [21]. Mackie et al. conducted a pilot study with the same construct for malignant melanoma. HSV-1716 was applied subcutaneously into melanoma nodules. No toxicity or virus shedding was observed. Pathological workup showed necrosis within excised tumor tissue from three patients. Further, signs of viral replication within the samples were observed [22]. Intravenous injections in pediatric and young adult patients (11–30 years) with recurrent or progressive non-CNS solid tumors were also well tolerated, as no dose-limiting toxicities or shedding of the virus (monitored with HSV-1 cultures and PCR from patient samples) were observed. Due to the small cohort size of nine patients and varying therapy regimens pre- and post-virus treatment, no conclusion regarding the efficacy of HSV-1716 could be drawn [20].
