*4.1. Oncolytic Herpes Simplex Virus*

Oncolytic HSV-1 (oHSV) is an enveloped double-stranded DNA virus that belongs to the alpha-herpesvirus subfamily [99]. It is a neurotropic virus and therefore requires engineering for tumor-restricted replication [100]. Modified oHSV-1 variants that have been tested in glioma patients are G207, G47∆, HSV1716 and rQNestin-34.5 [9]. Safety and feasibility of local oHSV injection in GBM was shown in two phase 1 trials testing G207 and HSV1716 [7,8]. However, in both studies viral replication was detected in only a few patients; 3 out of 6 and 2 out of 12 patients, respectively. These results suggest that the replication of the virus was restricted in some patients. In addition, seroconversion was observed in some patients indicating that the antiviral immune response may have contributed to the rapid clearance of the virus [7,8]. In an effort to understand these restricting mechanisms, Peters et al. studied G207 infection in vitro and found glioma stem cells (GSCs) to be non-permissive to infection [101]. G207 virus contains mutations in both copies of the γ34.5 gene to prevent neurovirulence, however, in GSCs this deletion results in a translational shut down preventing the production of progeny virions [101]. Other oHSV-1 variants designed to express the γ34.5 protein under a tumor-specific promoter such as the rQNestin-34.5, might enhance the oncolytic activity of the virus in GSCs [10].

Another modified HSV-1 is Talimogene laherparepvec (T-VEC) which is the first Food and Drug Administration (FDA) approved oncolytic virus and is indicated for treatment of patients with advanced melanoma [102]. Numerous clinical trials have employed T-VEC, however, no biomarkers for response have been described thus far. In a clinical study in melanoma patients, a favorable outcome was observed in a subgroup of patients with unresectable Stage III or IV M1a disease [103]. Recently, an in vitro study in melanoma cell lines revealed that STING expression can restrict T-VEC-mediated oncolysis and loss of its expression may confer sensitivity to oncolysis [104].
