Name: transarterial administration of oncolytic viruses for locoregional therapy of orthotopic hcc in rats
Uploaded: 2016-04-15T13:00:00
Description: Watch this Scientific Journal Video about Transarterial Administration of Oncolytic Viruses for Locoregional Therapy of Orthotopic HCC in Rats at JoVE.com

This work is supported by the SFB 824 subprojects C6 and C7 (DFG Sonderforschungsbereich 824), German Research Foundation, Bonn, Germany.

Note: The following steps have been performed in accordance with the guidelines of our institution and the local government of Bavaria, Germany. All attempts to reproduce this protocol must be made in adherence with the local guidelines for the humane treatment of animals, as dictated by local animal care and use committee. For example, many institutes require that sterile gloves are worn during rodent surgery.&#160;Furthermore, work with viruses must be performed according to local regulations, taking care for personal ...

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	<li>Murray, C. J., Lopez, A. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Evidence-based+health+policy+-+lessons+from+the+Global+Burden+of+Disease+Study.">Evidence-based health policy - lessons from the Global Burden of Disease Study.</a> Science. 274, 740-743 (1996).</li><li>Parkin, D. M., Bray, F., Ferlay, J., Pisani, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Estimating+the+world+cancer+burden:+Globocan+2000.">Estimating the world cancer burden: Globocan 2000.</a> Int J Cancer. 94, 153-156 (2001).</li><li>Bruix, J., Sala, M., Llovet, J. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Chemoembolization+for+hepatocellular+carcinoma.">Chemoembolization for hepatocellular carcinoma.</a> Gastroenterology. 127, 179-188 (2004).</li><li>Miraglia, R., Pietrosi, G., Maruzzelli, L., Petridis, I., Caruso, S., Marrone, G., Mamone, G., Vizzini, G., Luca, A., Gridelli, B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Efficacy+of+transcatheter+embolization/chemoembolization+(TAE/TACE)+for+the+treatment+of+single+hepatocellular+carcinoma.">Efficacy of transcatheter embolization/chemoembolization (TAE/TACE) for the treatment of single hepatocellular carcinoma.</a> World J Gastroenterol. 13, 2952-2955 (2007).</li><li>Breedis, C., Young, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+blood+supply+of+neoplasms+in+the+liver.">The blood supply of neoplasms in the liver.</a> Am J Pathol. 30, 969-977 (1954).</li><li>Nakashima, T., Kojiro, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Pathologic+characteristics+of+hepatocellular+carcinoma.">Pathologic characteristics of hepatocellular carcinoma.</a> Semin Liver Dis. 6, 259-266 (1986).</li><li>Heo, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Randomized+dose-finding+clinical+trial+of+oncolytic+immunotherapeutic+vaccinia+JX-594+in+liver+cancer.">Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer.</a> Nat Med. 19, 329-336 (2013).</li><li>Altomonte, J., Marozin, S., Schmid, R. M., Ebert, O. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Engineered+newcastle+disease+virus+as+an+improved+oncolytic+agent+against+hepatocellular+carcinoma.">Engineered newcastle disease virus as an improved oncolytic agent against hepatocellular carcinoma.</a> Mol Ther. 18, 275-284 (2010).</li><li>Shinozaki, K., Ebert, O., Kournioti, C., Tai, Y. S., Woo, S. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Oncolysis+of+multifocal+hepatocellular+carcinoma+in+the+rat+liver+by+hepatic+artery+infusion+of+vesicular+stomatitis+virus.">Oncolysis of multifocal hepatocellular carcinoma in the rat liver by hepatic artery infusion of vesicular stomatitis virus.</a> Mol Ther. 9, 368-376 (2004).</li><li>Shinozaki, K., Ebert, O., Woo, S. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Eradication+of+advanced+hepatocellular+carcinoma+in+rats+via+repeated+hepatic+arterial+infusions+of+recombinant+VSV.">Eradication of advanced hepatocellular carcinoma in rats via repeated hepatic arterial infusions of recombinant VSV.</a> Hepatology. 41, 196-203 (2005).</li><li>Altomonte, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synergistic+antitumor+effects+of+transarterial+viroembolization+for+multifocal+hepatocellular+carcinoma+in+rats.">Synergistic antitumor effects of transarterial viroembolization for multifocal hepatocellular carcinoma in rats.</a> Hepatology. 48, 1864-1873 (2008).</li></ol>

Although direct intratumoral injection is undoubtedly the simplest method to result in efficient tumor transduction of a single tumor nodule, hepatic arterial infusion represents an ideal administration route to target multifocal, orthotopic HCC. This method has proven to be both safe and effective for treating HCC in immune competent rats with oncolytic viruses. Furthermore, since HCC patients are routinely treated by transarterial application of chemoembolization, the method described here is readily translatable to ...

Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer worldwide, and the third leading cause of cancer-related death, making it a significant health concern1,2. For patients who are not eligible for tumor resection, or those awaiting liver transplantation, locoregional therapy involving transarterial embolization (TAE) or transarterial chemoembolization (TACE) are applied as standard palliative care3,4. These therapies exploit the unique feature of dual blood supply in the liver whereby tumors are fed almost exclusively by hepatic arterial blood flow, while the surrounding liver receives the majority of its blood supply from the portal vein5,6.
Due to the extremely limited efficacies of established therapies for HCC, oncolytic viruses have emerged as promising alternative therapeutics. JX-594, recently renamed Pexa-Vec, is a thymidine kinase-deleted vaccinia vector, armed with granulocyte-macrophage colony-stimulating factor (GM-CSF), which has completed phase II clinical trial for HCC7. More recently, a recombinant vesicular stomatitis virus vector (VSV) expressing human interferon-beta has entered a phase I clinical trial for sorafenib-refractory HCC (NCT01628640). As oncolytic viruses move closer to obtaining approval for clinical application for HCC in patients, the need for an effective administration route to target multifocal disease is evident. While systemic delivery is largely ineffective due to inefficient tumor transduction, intratumoral applications could limit the efficacy of the therapy to the injected tumor, leaving uninjectable microscopic lesions susceptible to disease progression.
We have established a method of isolating the hepatic artery in rats to administer oncolytic virus therapy in a locoregional manner to target orthotopic HCC. We have demonstrated that this administration route results in safe and effective transduction of multifocal HCC nodules, resulting in significant survival prolongation in immune competent rats8-10. Here, we describe the method of accessing, dissecting, and injecting into the hepatic artery in rats. A scheme of the procedure is shown in Figure 1 (previously published9)

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transarterial administration of oncolytic viruses for locoregional therapy of orthotopic hcc in rats

Hepatocellular carcinoma (HCC) is a disease with limited treatment options and poor prognosis. In recent years, oncolytic virotherapies have proven themselves to be potentially powerful tools to fight malignancy. Due to the unique dual blood supply in the liver, it is possible to apply therapies locally to orthotopic liver tumors, which are predominantly fed by arterial blood flow. We have previously demonstrated that hepatic arterial delivery of oncolytic viruses results in safe and efficient transduction efficiency of multifocal HCC lesions, resulting in significant prolongation of survival in immune competent rats. This procedure closely mimics the application of transarterial embolization in patients, which is the standard palliative care provided to many HCC patients. The ability to administer tumor therapies through the hepatic artery in rats allows for a highly sophisticated preclinical model for evaluating novel viral vectors under development. Here we describe the detailed protocol for microdissection of the hepatic artery for infusion of oncolytic virus vectors to treat orthotopic HCC.

With experience, a nearly 100% success rate (meaning that the artery was successfully dissected and injected, and the animal survived surgery) can be achieved. However, the health status of the rat prior to surgery (degree of tumor burden, underlying liver function, etc.) will obviously play a role in the outcome of the surgical intervention. Following surgery, rats can be expected to experience transient weight loss and a slight, transient elevation of liver enzymes, even if buf...

Watch this Scientific Journal Video about Transarterial Administration of Oncolytic Viruses for Locoregional Therapy of Orthotopic HCC in Rats at JoVE.com

Transarterial Administration of Oncolytic Viruses for Locoregional Therapy of Orthotopic HCC in Rats

Oncolytic virotherapies are under development as novel therapeutics for the treatment of hepatocellular carcinoma (HCC). Here we describe a method for locoregional therapy of HCC via hepatic arterial administration of oncolytic virus.

Hepatocellular carcinoma (HCC) is a disease with limited treatment options and poor prognosis.  In recent years, oncolytic virotherapies have proven ...

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