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Oncolytic Virotherapy Development for Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a general primary liver malignancy and it becomes the third leading cause of cancer deaths, with over 500,000 people affected annually. Although great progress has been made in prevention techniques, screening, and novel technologies in both diagnostic and treatment, incidence and mortality continue to rise. There are several treatment modalities of HCC, of which orthotopic liver transplantation (OLT) and surgical resection are the most effective and curative. Currently, oncolytic viruses (OVs) offer the promise of selective cancer therapy via direct and immune-mediated mechanisms. Based on our well established oncolytic virus development platform OncoVirapy™, Creative Biolabs is capable of developing specific oncolytic virotherapy strategy, as well as providing oncolytic virus construction and validation services for the development of HCC.

Pathogenic Mechanism of HCC

Primary Hepatic Cancer (PHC) is one of the most general malignant tumors with 90-95% of liver cancer being HCC. Liver cancer displays no symptoms in the early stage; however, clinical symptoms are evident in the advanced stage, resulting in an unsatisfactory curative effect. For liver cancer diagnosis, α-fetoprotein (AFP) is usually jointly used with iconography and pathology in early clinical stage. The main etiological factors connected with HCC are infection with the hepatitis B (HBV) or C (HCV) viruses, as well as chronic inflammatory liver lesions, necrosis of hepatocytes and fibrosis, long-term exposure to high levels of AFBI or vinyl chloride in the diet. However, cirrhosis continues to be the most significant risk factor for the development of HCC regardless of etiology. Hence, it is very crucial to develop effective and efficient care for patients with liver disease and HCC. Besides TP53 and CTNNB1, which are the most extensively studied genes mutated in HCC, a wide range of molecular pathway deregulation is observed, such as TGF-β signaling pathway, HGF/c-MET signaling pathway, EGF signaling, RAS/MAPK pathway, WNT signaling and etc.

Oncolytic Virotherapy Development for Hepatocellular Carcinoma Fig 1. Schematic diagram of Immune-based combination approaches in hepatocellular carcinoma.. (Greten, T. F., 2013)

Oncolytic Viruses (OVs) for Hepatocellular Carcinoma

One of the important goals of antitumor therapies is to target tumor cells selectively and specifically, meantime, sparing adjacent healthy tissue from destruction. OVs have been considered to be useful anti-tumor agents that kill dividing tumor cells but not normal tissue. A number of OVs are being tested in preclinical models of HCC, with good evidence of direct and immune-mediated anti-tumor efficacy. The majority of the preclinical studies use adenoviruses and vesicular stomatitis virus (VSV) as the vector, on account of their natural ability to kill or target HCC cells. For example, VSV has intrinsic ability to infect cancer cells, in case of adenoviruses, which has excellent tropism towards hepatocytes. Nevertheless, many studies have used other viruses, such as measles vaccine virus (MeV), vaccinia virus (VV), herpes simplex virus (HSV), and newcastle disease virus (NDV).

Aiming at targeting and enhancing the therapeutic efficacy of viruses, a number of genes are engineered in their genome. Besides, the anticancer and immunotherapeutic efficacy of these viruses is measured in HCC cell lines and animal models. One successful case is JX-594 or Pexavec (GM-CSF encoding VV), a recombinant Wyeth strain vaccinia virus, which is the leading agent in HCC clinical trials, has shown evidence for significant benefit and earned orphan drug status. Besides, G47delta (oncolytic HSV) and G207 (oncolytic HSV) have been studied for the treatment of HCC, and both show great therapeutic efficacy. What’s more, a more advanced method for HCC is a combined therapy with immune checkpoint inhibitors (ICIs), for example, mAbs against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed death-ligand 1 (PD-L1), and/or programmed cell death protein 1(PD-1).

With the rapid progress of novel therapeutic strategies in HCC, oncolytic virus continues to hold promise as an effective treatment. Based on our advanced OncoVirapy™ platform, Creative Biolabs is confident in providing novel OVs and developing more efficient oncolytic virotherapy strategies for our customers.

Reference:

  1. Yoo, S. Y., (2017). “Oncolytic Virus-Based Immunotherapies for Hepatocellular Carcinoma.” Mediators of inflammation, 2017.
  2. Greten, T. F., (2013). “Hepatocellular carcinoma from an immunologic perspective.” Clinical Cancer Research, 19(24), 6678-6685.

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