Oncolytic herpes simplex virus vectors for cancer virotherapy

Abstract

Oncolytic herpes simplex virus type 1 (HSV-1) vectors are emerging as an effective and powerful therapeutic approach for cancer. Replication-competent HSV-1 vectors with mutations in genes that affect viral replication, neuropathogenicity, and immune evasiveness have been developed and tested for their safety and efficacy in a variety of mouse models. Evidence to-date following administration into the brain attests to their safety, an important observation in light of the neuropathogenicity of the virus. Phase I clinical traits of three vectors, G207, 1716, and NV1020, are either ongoing or completed, with no adverse events attributed to the virus. These and other HSV-1 vectors are effective against a myriad of solid tumors in mice, including glioma, melanoma, breast, prostate, colon, ovarian, and pancreatic cancer. Enhancement of activity was observed when HSV-1 vectors were used in combination with traditional therapies such as radiotherapy and chemotherapy, providing an attractive strategy to pursue in the clinic. Oncolytic HSV-1 vectors expressing ''suicide'' genes (thymidine kinase, cytosine deaminase, rat cytochrome P450) or immunostimulatory genes (IL-12, GM-CSF, etc.) have been constructed to maximize tumor destruction through multimodal therapeutic mechanisms. Further advances in virus delivery and tumor specificity should improve the likelihood for successful translation to the clinic.

Impact of novel oncolytic virus HF10 on cellular components of the tumor microenviroment in patients with recurrent breast cancer

“…Herpes simplex virus type 1 (HSV 1) is an ideal candidate for oncolytic viral therapy because of the following reasons: (a) it infects a broad range of hosts; (b) it causes lyses of the host cell at the end of viral replication; (c) it has a very large genome and therefore harbors many non-essential genes, mostly related to neuroinvasiveness that are expendable and can be replaced during the recombinant engineering process; (d) it can be controlled by antiviral drugs in the event of uncontrolled replication; and (e) its genome remains as an episome and does not incorporate in to the host genome, avoiding the risk of introducing mutations. 15 A unique and spontaneously mutated and naturally mutated HSV 1, HF10, has been demonstrated to be an effective oncolytic agent in preclinical contexts including peritoneal dissemination models, breast cancer xenografts and malignant melanoma models. [16][17][18][19] In all these studies, HF10 has been effective in tumor lyses.…”

Safety and biodistribution studies of an HSV multigene vector following intracranial delivery to non-human primates

“…Tumor cell killing is achieved by lytic virus growth, and thus these mutants have been referred to as oncolytic viruses. 27,28 The safety and biodistribution of oncolytic HSV viruses have been examined in both rodents and non-human primates following intracranial administration. The oncolytic HSV virus G207, for example, is deleted for g34.5 and UL39 (the large subunit of the viral ribonucleotide reductase) and is nonpathogenic 29,30 following intracerebral inoculation of mice and non-human primates and viral genomes remained localized to the injection site.…”

Clinical development directions in oncolytic viral therapy

“…One modification involved inactivation of viral gene ICP6, which encodes the large subunit of ribonucleotide reductase, an enzyme required for viral DNA replication. [77][78][79][80] This enzyme is expressed abundantly in rapidly dividing tumor cells but is sparse in normal cells. As a consequence, the ICP6 gene modified HSV-1 replicates selectively in tumor cells.…”

“…[107][108][109][110][111][112] Additionally, combination of HSV mutants with chemotherapy or radiotherapy has demonstrated enhanced antitumor activity. 80,101,[113][114][115][116][117][118] Radiation increased the anticancer activity of HSV when used in pancreatic, glioblastoma and cervical cancer models 119 but did not alter the antitumor effect of HSV in prostate cancer. However, high-dose radiation combined with oncolytic HSV virus did improve efficacy in other prostate cancer models.…”