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Virotherapy as a Key to Cancer Treatment
Viruses can be harnessed to infect, multiply within, and subsequently lyse cancer cells.!--h2>
Routinely prescribed for most types of cancer, chemotherapy targets fast-growing cells, like those typically found in rapidly growing tumors. But although chemotherapy can shrink tumors, they often grow back and become resistant, or refractory to the treatment.
To combat this resistance, chemotherapy is now often used in combination with other treatments that have different mechanisms for attacking and killing cancer cells. Doctors must be cautious when combining treatments to ensure the regimen does not become too toxic for patients to tolerate. The goal is to introduce drugs that can be used synergistically with chemotherapy to not only extend life, but to improve quality of life while undergoing treatment.
One promising approach is known as virotherapy or oncolytic virus therapy. This involves the conversion of viruses into cancer-fighting agents by reprogramming them to attack cancerous cells, while healthy cells remain relatively undamaged. Specifically, viruses can be harnessed to infect, multiply within, and subsequently lyse cancer cells; the drug targets the tumor and protects normal tissue.
Several types of oncolytic viruses have been developed to date. These include the adenovirus, which is a nonenveloped virus with a double-stranded, linear DNA genome that forms particles that are 70 to 90 nm in size. There have been multiple engineered versions of this virus in clinical trials, including Onyx-015 and H101. The latter has been approved in China and is sold by Shanghai Sunway Biotech.
A second form of oncolytic virus is Newcastle-disease virus (NDV). This is an enveloped virus with a single-stranded, negative-sense RNA genome that forms pleiomorphic particles ranging from 150 to 300 nm. Naturally attenuated versions, such as PV701, are in clinical development. Although still in Phase I testing, slow virus infusion rather than injection seems to mitigate side effects. The Maryland-based Wellstat Biologics reported positive Phase I open-label data for PV701, but Phase II data are not yet available.
Poxviruses are a family of enveloped viruses that contain a double-stranded, linear DNA genome and form particles that are 200 nm in diameter and 300 nm in length. Myxoma and vaccinia are family members that are under therapeutic development. Among several candidates, the most advanced poxvirus is Jennerex’ JX-594; in November 2011, Jennerex presented final data from a randomized dose-ranging Phase II clinical trial of JX-594 in patients with advanced liver cancer showing a statistically significant benefit in overall survival for the high JX-594 dose group versus the low dose group. A Phase IIb trial in liver cancer is now underway.
It may come as a surprise to some that the herpes simplex virus is also under consideration as an oncolytic virus. This is an enveloped virus with a double-stranded, linear DNA genome that forms particles that are 150 to 200 nm in diameter. Many engineered versions are in clinical trials for the treatment of multiple cancer forms, the most advanced of which is probably BioVex’ (now part of Amgen) OncoVEX, a modified herpes simplex virus containing genes encoding GM-CSF and undergoing Phase III testing in both melanoma and head & neck cancer. Other earlier-stage oncolytic viruses have included Germany-based Medigene’s G207 (targeted brain cancer) and NV1020 (targeted liver metastasis from colorectal cancer), though neither agent is active in Medigene’s pipeline, and UK-based Virttu Biologics’ HSV-1716 (Seprehvir) has undergone Phase I studies in squamous cell carcinoma of the head and neck, and in malignant melanoma.
Picornaviruses are a family of nonenveloped viruses with single-stranded, positive-sense RNA genomes that form particles that range from 18 to 30 nm. Members of this family that are being tested as oncolytic therapeutics include coxsackieviruses and engineered versions of poliovirus. The latter is in development at a few locations, including research institutes at Duke University and Stony Brook University, and has shown some preclinical efficacy against GBM and neuroblastoma. The firm Viralytics is developing the coxsackievirus A21 (CAVATAK) in a Phase II advanced melanoma study, and smaller Phase I trials are also active.
Vesicular stomatitis virus (VSV) is an enveloped virus with a single-stranded, negative-sense RNA that forms 65 to 185 nm bullet-shaped particles. This virus is still in the research stage; constructs have been tested at the Mount Sinai School of Medicine in New York.
Another form of oncolytic virus is the reovirus. This is a nonenveloped virus with a double-stranded, segmented RNA genome that forms particles that are 60 to 90 nm. The reovirus preferentially replicates in cancer cells that feature a common mutation known as an “activated Ras pathway,” while sparing normal cells. This makes it intrinsically tumor selective without the need for any genetic manipulation.
Oncolytics Biotech has developed a drug, REOLYSIN, from the naturally occurring reovirus that has demonstrated positive results in clinical trials on its own, but particularly in combination with certain chemotherapeutics. In December 2012, Oncolytics announced initial positive top-line data from a Phase III study examining REOLYSIN in combination with carboplatin and paclitaxel in patients with platinum-refractory, taxane-naïve head and neck cancers.
As we have seen, a number of oncolytic viruses have shown potential use in cancer treatment. Future research studies will give us an even clearer perspective on which, if any, of these viruses offer the most effective route toward a reliable and commercially viable complement to chemotherapy for oncologists and their patients.
Brad Thompson, Ph.D. is president and CEO of Oncolytics Biotech, a Calgary-based biotechnology company focused on the development of oncolytic viruses as potential cancer therapeutics.
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