Microscopy image showing vesicular stomatitis virions used for oncolytic therapies

Vesicular stomatitis virions used for oncolytic therapies

Project 4: Development of a New Viral Immunotherapeutic Approach for Hepatocellular Carcinoma

Lay summary

This project focuses on the development of genetically modified tumor-killing viruses, including the vesicular stomatitis virus, to treat hepatocellular carcinoma. Our project investigators are combining these viruses with clinically used immunotherapy treatments (immune checkpoint inhibitors) to leverage enhanced killing of the tumor by immune cells (T cells). In addition, we're engineering new viruses that will further enhance the immune response, testing them in laboratory models and then advancing the most promising candidates into clinical trials.

Scientific rationale

This research project in the Mayo Clinic Hepatobiliary SPORE is assessing the use of an oncolytic virus expressing an immune stimulatory gene in combination with checkpoint inhibitor antibodies in animal models and in an early-phase clinical trial. We're engineering a next-generation oncolytic viral platform tailored to the treatment of hepatocellular carcinoma.

This project builds on an ongoing phase 1 clinical trial for hepatocellular carcinoma in which oncolytic vesicular stomatitis virus expressing the immune stimulatory gene interferon-β (IFN-β) is injected directly into liver cancers.

We have established animal models that demonstrate that the combination of a systemic checkpoint inhibitor and an intratumorally delivered oncolytic virus can significantly improve survival outcomes over either modality alone, and that survival benefit is associated with a striking improvement in anti-tumor Th1 memory responses.

Hypothesis

We hypothesize that the oncolytic vesicular stomatitis virus provides a complementary mechanism of action to immune checkpoint inhibition and that this combination can be used to effectively treat hepatocellular carcinoma.

Project aims

The aims of this research project are to:

  • Perform a phase 1B clinical study to test the combination of vesicular stomatitis virus expressing the immune stimulatory gene IFN-β in combination with the PDL1 antibody durvalumab in study participants with advanced hepatocellular carcinoma
  • Determine the optimal dosing regimens of combination checkpoint blockade therapy with oncolytic vesicular stomatitis virus expressing the immune stimulatory gene IFN-β
  • Develop a next-generation vesicular stomatitis virus platform expressing tumor-associated antigens that is specifically tailored to hepatocellular carcinoma