**1. Introduction**

In the past decade, immunotherapeutic drugs for oncology have revolutionized the field. The landscape of immunotherapeutic drugs has been spearheaded by immune checkpoint inhibition [1–3], as well as CAR (chimeric antigen receptor)-T-cell therapy [4,5], suicide-gene approaches [6], and a range of other agents, e.g., tumor antigen vaccinations [7]. In addition to these, oncolytic viruses (OVs) have emerged as an important part of the immunotherapeutic armory (Figure 1).

OVs infect tumor cells and cause their lysis leading to a release of tumor-specific antigens as well as neoantigens. Antigen presentation and virus induced activation of the innate immune cells in turn trigger the activation of tumor-specific T-cells.

Among OVs in clinical trials, Herpes simplex virus 1 (HSV-1)-derived agents are some of the most widely tested viral vectors and have also been thoroughly investigated in numerous pre-clinical studies [8]. HSV-1 is a double-stranded neurotropic DNA-virus [9,10]; the wild-type virus in humans can cause mucocutaneous lesions, keratoconjunctivitis, encephalitis, and respiratory infections [10]. Its large genome of 150 kb [11], infectivity, and lytic activity present ideal properties for a potent engineerable OV: HSV-1 can infect a variety of cell types and cause lysis; its comparatively large genome facilitates modifications that can enhance anti-tumorigenic features and reduce neurovirulence [12] and it can easily be inactivated by the anti-herpetic drugs ganciclovir, acyclovir, or valacyclovir. To date,

17 strains of HSV-1 are known [11]. Multiple genetic modifications of HSV-1 have been described that alter infectiousness, neurovirulence, and lytic activity (Table 1). Engineering strategies aim at (a) preventing infection of the nervous system, e.g., by deleting the neurovirulence gene γ*34.5*/*RL1* [13] (b) enhancing tumor-selectivity, e.g., by deleting the ribonucleotide reductase expressing gene *ICP6* [14] and (c) increasing immunogenicity by adding genes to express immunostimulatory mediators, such as GM-CSF [15] and IL-12 [16,17] or counteract T-cell exhaustion by arming the HSV-genome with anti-CTLA-4 and anti-PD-1 targeting antibody sequences [18]. Current oHSVs tested in published clinical trials include HSV1716, G207, HF10, NV1020, and talimogene laherparepvec (T-Vec), which is until now the most thoroughly investigated HSV-1 related OV and in 2015 became the first OV to gain FDA-approval, after a successful trial in advanced melanoma [13]. There are several additional oHSVs that are currently under clinical and re-clinical investigation. This review aims to give an overview *Cancers* over the state of clinical applications of oncolytic viral therapy with oHSV-1 and future directions. **2020**, *12* 2 of 19

**Figure 1.** Mechanism of oncolytic virus therapy and interaction with the immune system. **Figure 1.** Mechanism of oncolytic virus therapy and interaction with the immune system.


OVs infect tumor cells and cause their lysis leading to a release of tumor‐specific antigens as well **Table 1.** Oncolytic Herpes viruses tested in oncology clinical trials to date.

re‐clinical investigation. This review aims to give an overview over the state of clinical applications

**Table 1.** Oncolytic Herpes viruses tested in oncology clinical trials to date.

without promoter possibly reducing neurovirulence [16]

deletion of *γ34.5/RL1* reducing neurovirulence [15]

*lacZ* sequence at *ICP6/UL39* reducing ribonucleotide reductase activity [14]

of oncolytic viral therapy with oHSV‐1 and future directions.

insertion of the Escherichia coli

two incomplete *UL56* copies

G207

HF10

**Virus Strain Modifications Aim**

1716 deletion of *γ34.5/RL1* reducing neurovirulence [15]

deletion in the Bam HI‐B fragment unknown

ribonucleotide reductase expressing gene *ICP6* [14] and (c) increasing immunogenicity by adding genes to express immunostimulatory mediators, such as GM‐CSF [15] and IL‐12 [16,17] or counteract T‐cell exhaustion by arming the HSV‐genome with anti‐CTLA‐4 and anti‐PD‐1 targeting antibody sequences [18]. Current oHSVs tested in published clinical trials include HSV1716, G207, HF10,


### **Table 1.** *Cont*.
