Oncolytic Herpes Simplex Virus

Oncolytic herpes simplex virus (oHSV) is one of oncolytic viruses being studied in cancer therapeutic research and several oHSVs have been investigated in clinical trials. Due to its pathogenicity, at least 8 different HSV-1 genes which include TK (UL23), ICP6 (UL39), ICP34.5, and Us3 should be deleted or mutated for safety consideration. As a consequence, with a unique mechanism, the oHSV can selectively replicate in and kill cancer cells without the permission to normal tissue. For years of experience in immunology and oncology, Creative Biolabs has established a comprehensive platform called OncoVirapy™ for providing oncolytic virus development service. By virtue of OncoVirapy™, we are able to design, engineer and generate the most efficacious oncolytic herpes viral vector and viral particles.

Reference Oncolytic Virus

When it comes to oncolytic HSV, the first representative is Talimogene laherparepvec (T-Vec), an oncolytic agent approved by the US Food and Drug Administration for the treatment of melanoma.

Biologically, T-Vec is an attenuated HSV type 1 by deleting viral γ34.5 and α47 genes, while, inserting two copies of human granulocyte-macrophage colony-stimulating factor (GM-CSF) genes. The deletion of the γ34.5 gene can attenuate pathogenicity of the virus and allow for selective replication only in cancer cells. α47 gene deletion is mainly aimed to enhance antigen presentation since that viral infected cell protein 47 (encoded by α47 gene) functions to reduce immune destruction. Meanwhile, absence of α47 gene also results in immediate and increased expression of unique short 11 (US 11), leading to enhanced replication of T-Vec in tumor cells. More importantly, two copies of normal GM-CSF gene insertion allows for human GM-CSF expression, which greatly increases the accumulation of dendritic cells at tumor site, enabling a strengthened tumor-antigen presentation and antitumor immunity.

Currently, T-Vec can be applied both in monotherapy and in combination with other immunotherapies for the treatment of melanoma as well as other malignant tumors.

Fig.2 Anti-tumor effect of Talimogene laherparepvec. (Ott k, 2016)

• Oncolytic Herpes Simplex Virus Introduction

Herpes simplex virus-1 (HSV-1) contains four main components, a core that contains double-stranded DNA (dsDNA) which is arranged by two unique sequences: Unique Long (UL) and Unique Short (US), an icosadeltahedral capsid, an amorphous tegument, and an outer lipid bilayer envelope with glycoprotein spikes for viral entry. Some characteristics including large foreign genes capacity, neural sensitivity tropism and high titers of manufacture enable HSV-1 to be used as a viral-delivery candidate for cancer treatment. Through genetic engineering, the HSV-1 can be designed as a replication-competent virus. For instance, the mutation in the viral thymidine kinase (TK) gene has shown the killing of glioma cells in vitro and in vivo. Also, a mutation in the ICP34.5 gene results in replication failure in normal cells. HSVs with ICP6 gene mutations can only replicate in dividing cells like tumor cells. 

• Armed Oncolytic Herpes Simplex Virus

Creative Biolabs provides various armed oncolytic herpes simplex viruses for our customers to achieve research and treatment purpose. The anti-sense sequence of miRNA (miRT) maintains potent virulence in cancer cells. The miRT includes but is not limited to miR-122T which is specific to hepatocellular carcinoma (HCC) cells, miR-182T which is specific to uveal melanoma (UM) cells. To enhance viral versatility, the siRNA and shRNA like siNotch1, shSurvivin, shMPP1 and shVEGF can be delivered to target abnormal genes. The immune checkpoint inhibitory and the cytokine/chemokine can be expressed through high-capacity oHSV by precise design; tropism can also be modified for more expansion therapeutic window as well. We also provide customized oncolytic herpes simplex virus and proof-of-concept validation study for the oncolytic virus. With the increasing experience and knowledge of HSV system, coupled with the OncoVirapy™ platform, Creative Biolabs commits to developing efficacious oncolytic herpes simplex virus and enabling wider applications in oncolytic virotherapy of cancers. Please don’t hesitate to contact us for more information and quotation.

Reference:

1. Ott, P.A.; Hodi, F.S. Talimogene Laherparepvec for the Treatment of Advanced Melanoma. Clinical Cancer Research. 2016, 22(13): 3127-3131.

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