Research Overview

Immune-modulatory Gene Therapy for Metastatic Disease

Gene therapy is an emerging biomedical discipline that will find applications in the treatment of a wide variety of diseases. A number of recombinant gene transfer vector systems have been developed in the past few years to achieve persistent gene transfer and expression in various animal models of disease. Because of its high efficiency in gene transfer and expression, the replication-defective recombinant adenovirus is an ideal vector to deliver suicide genes that cause tumor destruction, and the treatment strategy was shown to be effective against a variety of localized cancers including cancers in the brain, head and neck, colon, pancreas, ovary, bladder and prostate in laboratory animals.

In addition, adenovirus-mediated immunomodulatory gene delivery into the tumors induced robust anti-tumoral immune responses that were effective in rejecting a variety of solid tumors in laboratory animals, and several clinical translational trials against various cancer targets are currently being conducted at Mount Sinai.

Furthermore, it was discovered that active genetic immunization using gene-expressing vectors and recombinant proteins that simultaneously induce an innate immune response and tumor-specific cytolytic T lymphocytes are synergistic in tumor rejection. Greater than 80% of the treated animals with various cancer targets became long-term survivors that are tumor-free, and the anti-tumor effect is also systemic as it rejected pre-established multi-focal metastases in the lung. The equivalent gene vector and recombinant protein that target human tumors have already been constructed and this novel treatment paradigm will be tested in patients with various metastatic diseases at the Icahn School of Medicine in the coming years.

Oncolytic VSV Virotherapy for Liver Cancer

Most recently, it was discovered that many RNA viruses have the natural tendency to efficiently replicate specifically in tumor cells due to their attenuated responses to type I interferons. Of these, the Vesicular stomatitis Virus (VSV) is a particularly attractive oncolytic agent as its replication cycle in tumor cells is only 8-10 hours, which will permit extensive viral replication in tumors prior to the onset of anti-viral immune responses in the host.

One limitation to the field of oncolytic virotherapy has been the rapid cellular innate response to virus infection, and the virus is rapidly cleared from the tumor site after only 1-2 days. To overcome this limitation, a recombinant VSV vector that has been genetically engineered to express a heterologous viral chemokine binding protein gene that attenuate innate cellular immune responses in the lesions was constructed.

The novel recombinant virus vector has been proven effective in causing massive tumor destruction in laboratory animals bearing multi-focal Hepatocellular Carcinoma (HCC) and metastatic Colorectal Carcinoma (CRC) in their livers, which led to substantial survival prolongation and tumor rejection in half of the animals. Importantly, the recombinant virus does not cause systemic immune suppression in the animals and immune attenuation is restricted in the infected tumors. Biodistribution and pharmacology and toxicology studies have been completed in animals to support an Investigative New Drug application to the FDA, and a clinical translational trial for patients with advanced liver cancer will be initiated in 2011. Thus, gene therapy is rapidly developing into a novel biomedical discipline that can be productively applied in the treatment of both genetic and acquired disorders in humans, and it represents a fundamental form of molecular medicine that will have a major impact on health and healthcare for decades to come.


Savio L.C. Woo, PhD
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