|Oncolytic Viruses: Are They The Future of Cancer Therapy?|
|By Douglas W. Loe, PhD, MBA|
|Monday, 22 November 2010 01:42|
Chemotherapy—as any cancer patient will tell you—is not for the faint of heart, but it can kill many forms of cancer. Some 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, like those typically found in rapidly growing tumors. But while 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 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 virus targets tumors without affecting normal tissue.
Several types of oncolytic viruses have been developed to date. These include the adenovirus, which is a non-enveloped 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 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 private firm Wellstate Biologics has two Phase I open-label PV701 cancer trials ongoing.
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 is probably Jennerex’s JX-594, which is entering a Phase II liver cancer trial in partnership with Transgene (see below) and which could enter a Phase II colorectal cancer study imminently, testing JX-594 in patients refractory to Eli Lilly’s (NYSE: LLY ) leading EGFr-targeted antibody drug Erbitux. Interim data are already available from nine patients in a small Phase I/II liver cancer study showing disease stabilization in at least five patients when JX-594 is administered with Bayer’s approved liver cancer drug sorafenib (branded as Nexavar). JX-594 performed just as well in a separate Phase I liver cancer study where it was tested as monotherapy and not in combination with Nexavar. Interim data from 24 patients in that trial showed disease stabilization at two months in most JX-594-treated patients, providing solid evidence of JX-594 oncolytic virus potency at treating this cancer form.
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 GBM and neuroblastoma. The firm Viralytics is developing the coxsackievirus A21 in a Phase I advanced melanoma study.
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 Mt. 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 tumor 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% testing positive by adulthood.
Tumors bearing an activated Ras pathway cannot 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 signaling pathway, eventually killing the host cell and freeing the viral progeny that go on to infect and kill more Ras-activated tumor cells. When normal cells are infected with reovirus, the immune system can neutralize 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 signaling 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 tumor 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.
The above 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.
Calgary-based Oncolytics Biotech, Inc.(Nasdaq:ONCY) has developed a biologic agent, Reolysin, from naturallyoccurring reovirus. The virus 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 tumor shrinkage, without increasing adverse side effects. A pivotal 180-to-480-patient Phase III head and neck cancer study commenced this year and could generate survival data in a few years. 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 II clinical trials using Reolysin in combination with chemotherapy against a variety of advanced cancers. And based on solid evidence that Reolysin could be effective as an anticancer agent targeting tumor types with activated Ras pathway, Oncolytics Biotech and clinical collaborators are actively testing Reolysin in ovarian cancer, colorectal cancer (though only in patients harboring mutated Kras gene), melanoma, sarcoma, and pancreatic cancer, for which tumor response data could be available in a year or two.
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 four recently-launched anticancer therapies already on the market. One of these is erlotinib, branded as Tarceva, developed by OSI Pharmaceuticals and launched in 2004 by Roche/Genentech and OSI. An oral small molecule tyrosine kinase inhibitor drug 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 $1.2 billion in 2009. Another is the immunomodulatory and anti-angiogenic drug thalidomide (branded as Thalomid), developed by Celgene and launched in 2003 for treating multiple myeloma, which enjoyed sales of $224 million that first year and reached $505 million by 2008. A third is lenalidomide (branded as Revlimid and also developed by Celgene), a drug structurally related to Thalomid that generated even more robust sales growth after its launch in 2006, achieving blockbuster sales in 2008 of $1.3 billion that grew to $1.7 billion last year. And a fourth is the oral alkylating agent temozolamide, branded as Temodar by Schering-Plough (now part of Merck) and approved as a glioblastoma (brain cancer) drug; Temodar generated $180 million in sales in 2001 that grew to $703 million in 2006 (its first full-year of sales in the U.S.) and exceeded US$1 billion in 2009. Though survival benefit of 11 weeks is modest, the drug (along with Roche’s Avastin) is still standard-of-care for patients with advanced brain cancer.
Partners and capital markets are now recognizing value in oncolytic viruses
The year-over-year, steadily increasing demand for the four drugs described above provides supporting evidence that demand for new and effective agents in oncology remains strong, giving us confidence that Reolysin could be similarly embraced if it performs well in Phase III testing. We are optimistic that global oncology-focused pharmaceutical firms will be keen to partner with Oncolytics once Reolysin Phase III head and neck cancer data are available, if not before, and capital markets are exhibiting optimism in Reolysin’s medical prospects through the company’s share price strength this year and through well-subscribed equity offerings in 2009/10.
And in other commercial advances in oncolytic virus development, Jennerex’s JX-594 is now partnered with the French biotechnology firm Transgene in a $116 million alliance that could pay Jennerex a double-digit royalty on future JX-594 sales if the drug performs well in pivotal liver cancer or colorectal cancer trials, or in other cancer indications contemplated in the alliance. The Transgene alliance seems to be focused on European and Middle East marketing rights and thus provides an opportunity for U.S. or Japan-based firms to partner with Jennerex in those regions.
As we have seen above, there are a number of oncolytic viruses that have shown potential use in cancer treatment and demand for more effective agents is strong. 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.
About the Author
Douglas W. Loe, PhD, MBA authored and submitted this article solely for the purpose of providing key expert analysis and opinion. No compensation was exchanged by either party in consideration for the publication of this material.
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