Oncolytic Herpes Simplex Virus

• Safety

  HSV-1 can be genetically-engineered or significantly attenuated to confer safety by deleting or mutating some virulence genes.

• Tumor targeting specificity

  HSV-1 genome has many genes that can be deleted, replaced or mutated to confer tumor-targeting specificity through tumor-selective receptor binding and transcriptional- or post-transcriptional miRNA-targeting, respectively.

• "Armed" with transgenes

  HSV can be "armed" with transgenes that are: reporters, to track virus replication and spread; cytotoxic, to kill uninfected tumor cells; immune modulatory, to stimulate antitumor immunity; or tumor microenvironment altering, to enhance virus spread or to inhibit tumor growth.

  Fig.1 Map of HSV-1 genome and schematic representation of essential genes and non-essential genes. (Artusi, 2018)

Oncolytic virotherapy with mutants derived from HSV-1 exhibits significant antitumor effects in preclinical models. Several mutants have now been tested in clinical trials for a variety of cancer types, such as colorectal cancer, melanoma and osteosarcoma. Excitingly, some mutants have been found to be safe and effective. Table.1 listed several common genetic alterations of oHSVs.

Fig.1 Map of HSV-1 genome and schematic representation of essential genes and non-essential genes. (Artusi, 2018)

• Thymidine kinase/UL23 (E)

  HSV-1 thymidine kinase (TK) is a multifunctional enzyme that catalyzes the creation of deoxythymidine 5'-phosphate (dTMP) from deoxythymidine, as well as phosphorylating deoxycytidine and nucleoside analogs, creating precursors for viral DNA synthesis. Loss of TK activity halts HSV-1 replication in nondividing cells, making TK mutants safer than wild type HSV-1. Dlsptk, an HSV-1 lacking TK, was the first genetically-engineered oncolytic virus devised to kill tumor cells while sparing normal cells.

• ICP6/UL39 (E)

  ICP6 is the large subunit of the viral ribonucleotide reductase, which transforms ribonucleotides into deoxyribonucleotides (dNMP) by reducing the 2'-COH group. ICP6 is essential for HSV replication in noncycling cells, making ICP6-null oHSVs selective for dividing cells.

• γ34.5 (ICP34.5)/RL1 (L)

  γ34.5, one of the most frequently mutated genes for creating oHSVs, has many functions. HSV-1 is diploid for the γ34.5 gene, and mature virions contain the protein in their tegument in order to deliver it upon entry. Attenuation of both copies of this gene leads to a reduction of neurovirulence associated with HSV-1 in vitro and in vivo. Despite the reduced replication in normal cells, HSV-1 virions deleted for ICP34.5 efficiently replicate in and are cytotoxic to a majority of glioma cell lines and primary tumor-derived cells.

• ICP47

  ICP47 deletion enhances anti-tumor efficacy while retaining safety characteristics. G47Δ showed efficacy in all solid tumor models tested in vivo, such as hepatocellular carcinoma, schwannoma, prostate cancer, nasopharyngeal carcinoma, glioma, thyroid carcinoma, colorectal cancer, breast cancer and malignant peripheral nerve sheath tumor.

• ICP0 (IE)

  ICP0 encodes a RING finger ubiquitin E3 ligase that targets cellular proteins. ICP0-null HSV-1 is extremely sensitive to IFN and PML-mediated disruption of the viral lifecycle. ICP0-null HSV-1 is extremely sensitive to IFN and PML-mediated disruption of the viral lifecycle.

• UL56 (L)

  UL56 is another gene associated with pathogenicity and neuroinvasiveness. UL56 is a good candidate for mutation when creating a safer oHSV. In addition, it may contribute to tumor selectivity.