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Forging Ahead

Chemotherapy – as any cancer patient will tell you – is not for the faint of heart, but it can kill many forms of cancer. A form of chemotherapy, originally discovered as a cancer treatment almost 70 years ago, is still routinely prescribed for most types of the disease. The treatment works by targeting fast-growing cells, such as those typically found in rapidly growing tumours. But while chemotherapy can shrink tumours, 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 that 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.

THE POTENTIAL OF ONCOLYTIC VIRUSES

One approach that has proven quite promising is known as oncolytic virotherapeutics. Here, viruses are harnessed to infect, multiply within and subsequently lyse cancer cells. The drug targets the tumour 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 are 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 singlestranded, 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 1 testing, slow virus infusion rather than injection seem to mitigate side effects. Maryland-based Wellstat Biologics reported positive Phase 1 open-label data for PV701, but Phase 2 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’s JX-594, for which positive Phase 2 liver cancer data were reported last year and a larger randomised Phase 2 liver cancer study is planned for 2011.

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’s (now part of Amgen) OncoVEX, a modified herpes simplex virus containing genes encoding GM-CSF, which is currently undergoing Phase 3 testing in both melanoma, and head and neck cancer. Other earlier-stage oncolytic viruses include Germany-based Medigene’s G207 (targeted brain cancer in Phase 2 testing), and NV1020 (targeted liver metastasis from colorectal cancer in Phase 2 testing) though neither agent is active in Medigene’s pipeline, and UK-based Crusade Laboratories’ HSV-1716 (Seprehvir) has undergone Phase 1 oral cancer testing and a clinician-sponsored Phase 1 CNS solid tumour study is underway.

Picornaviruses are a family of non-enveloped 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 glioblastoma multiforme and neuroblastoma. Viralytics is developing the coxsackievirus A21 (CAVATAK) in a Phase 2 advanced melanoma study and smaller Phase 1 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; two constructs have recently been tested at the Mount Sinai School of Medicine in New York.

REOVIRUSES: THE MOST PROMISING OPTION?

Finally, we come to what some consider the most promising form of oncolytic virus: the reovirus. This is a non-enveloped 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 tumour selective without the need for any genetic manipulation.

Reovirus is a virus with no known associated disease. It replicates in the cytoplasm and therefore does not integrate into the cell’s DNA. Reovirus is found everywhere in nature and has been isolated from untreated sewage, river and stagnant waters. Exposure to reovirus is common in humans, with half of all children by the age of 12 having been exposed and up to 100 per cent testing positive by adulthood.

Tumours bearing an activated Ras pathway can’t activate the anti-viral response mediated by the host cellular protein, PKR. Studies have shown that reovirus actively replicates in transformed cell lines with an active Ras signalling pathway, eventually killing the host cell and freeing the viral progeny that go on to infect and kill more tumour cells. When normal cells are infected with reovirus, the immune system can neutralise the virus. Approximately one-third of human cancers have activating mutations in the Ras gene itself, and it is possible that more than two-thirds of cancer cells have an activated Ras signalling pathway because of activating mutations in genes upstream or downstream of Ras.

HOW REOVIRUSES MIGHT HELP

While it has been demonstrated in animal studies that reovirus is capable of treating metastatic cancer in immunocompetent mice, it has also been shown that reovirus, used in conjunction with immunosuppressive drugs, can effectively prolong animal survival. Combining IV reovirus therapy with Cyclosporine A, an immune suppressant, significantly inhibited tumour regrowth. In a model of disseminated LLC metastatic lung cancer in C57BL mice, treatment with reovirus and either Cyclosporine A or T cell depleting antibodies (anti-CD4 and anti-CD8 Ab) led to an increase in survival compared to treatment with reovirus alone.

These results supported the development of clinical protocols in which immune suppressive drugs could be combined with a systemically administered reovirus in the treatment of cancer. The combination of reovirus with various chemotherapies in human colorectal cancer cell lines demonstrated synergistic cytotoxic activity. In addition to modulating the immune response, the use of chemotherapies along with reovirus treatment may enhance intratumoral spread of the virus.

One drug that has been developed from the naturally occurring reovirus is Reolysin from Oncolytics Biotech Inc. The drug has demonstrated impressive results in clinical trials on its own, but particularly in combination with certain chemotherapeutics. In preclinical studies in a wide variety of cancer cell lines, investigators found that when used together, reovirus and chemotherapy resulted in more efficient and synergistic anti-cancer activity than when each agent was used on its own.

These combinations are showing extremely good results in human trials, particularly in refractory head and neck cancer patients. Many head and neck cancer patients treated with a combination of Reolysin and chemotherapy to date have experienced dramatic and prolonged tumour shrinkage, without increasing adverse side effects. Non-small cell lung cancer (NSCLC) is another potential target for this treatment combination. The Cancer Therapy & Research Center at the University of Texas Health Science Center – a big proponent of oncolytic viruses – has committed to funding up to five Phase 2 clinical trials using Reolysin in combination with chemotherapy against a variety of advanced cancers.

CONCLUSION

It is difficult to provide a crystal-clear economic forecast for oncolytic viruses as a whole, but an indicator of their potential future sales earnings can be derived from examining two oncolytic brands already on the market. The first of these is Tarceva, which was introduced in 2004. An oral oncolytic that is prescribed for patients with advanced-stage non-small cell lung cancer, it earned $20 million in 2004, $387 million in 2005, and $813 million in 2006. Sales reached $1.215 billion in 2008. The second, Thalomid, which was sold at the beginning of 2003 for use in treating multiple myeloma, enjoyed sales of $224 million that first year and had reached $505 million by 2008. The year-on-year, steadily increasing demand for these two oncolytic drugs potentially translates into a similar growth market for the entire sector.

As we have seen above, there are a number of oncolytic viruses that 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.


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Douglas W Loe is a consistently top-ranked healthcare and biotechnology analyst. He has covered Canadian biotech since 2000, initially as part of the research team at Yorkton Securities (now Macquarie Capital Markets), and has been with Versant since autumn 2002 where he covers a broad spectrum of drug development, medical technology and healthcare services firms. Doug holds a MBA from Queen’s University and a PhD in biochemistry from the University of Guelph, working in the area of cancer chemotherapy and multidrug resistance, followed by postdoctoral training at the Queen’s University Cancer Research Institute. During his scientific career, he published multiple abstracts, peer-reviewed manuscripts and reviews related to P-glycoprotein and MRP-mediated multidrug resistance. Email: dloe@versantpartners.com
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