Virotherapy, or the use of oncolytic viruses (OVs) to kill cancer cells
by Chris Woollams
This article is about another ´Alternative´ Cancer Treatment. Namely, that of using common viruses to kill cancer cells whilst leaving healthy cells unharmed. Oncolytic viruses are live viruses that replicate selectively and, ideally, enthusiastically in tumour cells, but not in healthy cells. There are a number of strategies in, what is now called, virotherapeutics. Technical advances are increasing tumour specificity and replication rates and great advances have been made in the last decade. However, some viruses that replicate well in laboratory tests are much slower in real life situations where cancer tumours erect more barriers.
Recently, there has been much interest in a non-pathogenic ECHO-7 virotherapy called Rigvir, which has been used to treat melanoma but also a number of other cancers such as breast and prostate cancer. It is not ´approved´ for use in America or the UK, even though the development has been through full clinical trials in another EU member state - Latvia. Work was also completed in Germany (See Here).
One that has been approved (almost begrudgingly by the FDA in the USA is T-VEC again targeting melanoma. Work will now take place on other cancers with this Herpes virus.
Virotherapy has been around for 15 years or more - indeed we even have an article on the successes of their ´Virotherapy´ programme from the MD Anderson Cancer Center in Texas covering a couple of patients with lung cancer, who lived more than 10 years after treatment.
Early clinical trials have shown great potential, and some viruses are currently in late stage clinical trials.
Furthermore common viruses may be genetically modified to enhance their attack on cancer cells, and/or to prevent harm to healthy cells and/or to overcome cancer tumour barriers. Although they are most usually referred to as oncolytic viruses (OVs), they are sometimes erroneously called cancer vaccines. Genetic engineering has led to some of these viruses becoming a novel form of gene therapy. Some are modified to become genetic ´carriers´ to disrupt some particular genetic feature of the cancer.
Rarer cancers, and mainstream cancers
About 9 years ago CANCERactive ran a story about researchers lead by Professor Moira Brown in Scotland using the Herpes virus in an attempt to kill brain cancer cells (see Example 9). Her work has progressed and patients have seen extended survival times. Her team believes that the herpes virus could be used to treat many different types of cancer.
In Cancer Watch, our cancer research centre, we have brought you many more studies. Put ´viruses used to kill cancer cells´ into your Internet search engine and you will see that this is a huge and developing area of Alternative Cancer Treatment, especially in America where people with rarer cancers (for which orthodox medicine often offers little) are brought into a trial on many new ´alternative´ treatments with potential - like virotherapy, dendritic cell therapy and others. Some 20 viruses are in early stage trials. Nine viruses are in Phase I and phase II trials with ovarian cancer, for example.
In 2013 Cancer Watch covered research on prostate cancer where a genetic modification involves a protein which is cleaved by Prostate Specific Antigen (PSA) making the virus extremely aggressive to the cancer.
Moira Brown´s research team see no reason why their herpes virus should work with all manner of cancer tumours.
But matters are a little slower in Europe - In 2009 Ark Therapeutics issued results of a Phase III Clinical Trial on an adenoviral vector dubbed TK, but the marketing application has been rejected by the European Medicines agency for being underpowered and failing to show sufficient efficacy. They are making an appeal.
It is all very complex. One issue is to now start to pick some ´winners´ amongst the basic viruses, and some ´winners´ amongst the modified versions. In that way there can be more focus towards finding one really powerful treatment. Another issue is that off immunity: that of maximising the attack on cancer cells, but minimising any undesirable effects in the body.
This is not meant to be our usual type of article but more a briefing, providing some examples of work currently under development. What I observe is that virotherapy research is widespread and takes many different forms. Phase III Clinical Trials are in the offing, but the lack of them has not stopped some top cancer centres going ahead already and using the treatment on patients, especially with rarer cancers:
Example 1: In 2006 researchers at the Mayo Clinic were testing the use of the Measles virus. ´We are looking at better ways to treat some of the most lethal cancers´, said Dr. Eva Galanis, oncologist and lead researcher on the glioblastoma multiforme project in the measles virus investigation. ´We have shown in the laboratory and in several animal models that measles virus strains can significantly shrink glioma tumors and prolong animal survival´.
This Mayo Clinic work with strains of the measles virus was unique at the time. The called the viruses vaccines or oncolytic viruses. Early work looked at cancers including glioblastoma multiforme, recurrent ovarian cancer and multiple myeloma
Example 2: Dr. Kevin Harrington, working at The Royal Marsden Hospital, London for the Institute of Cancer Research, studied 17 patients found that use of the Herpes virus with chemotherapy and radiotherapy can help kill cancer cells in most patients. It does this in three ways: By direct attack on the cancer cells, multiplying inside them; the genetic modification is designed to produce a protein to activate the immune system; the virus itself causes a rapid increase in the immune system against it (and the cancer cells it is living in).
The treatment was most effective with early stage cancers - the study was with cancers of the head and neck area. 93% showed no recurrence of cancer after surgery and 82% of patients still did not show any recurrence of the disease more than two years later.
The herpes virus is genetically manipulated so that it attacks and thrives in cancer cells but cannot infect healthy cells.
The worry, of course, is that the genetically modified virus does cause health problems years later, maybe even to the population at large. (August 2010; Journal of Clinical Cancer Research).
Example 3: Researchers at Georgetown Lombardi Comprehensive Cancer Center, part of Georgetown University Medical Center, are conducting a clinical trial using the Reovirus. Normally, you have experienced this virus at least once by the age of 5, causing coughing and diarrhea, but sometimes no symptoms. Apparently, the researchers found that the virus grows like gangbusters inside cancer cells, because of a specific attribute of a cancer cell, namely that the Ras gene is dominant and making it divide paridly. In healthy cells the p53 gene suppresses the Ras gene. Researchers are currently conducting a Phase II Clinical Trial with small cell lung cancer patients. Again, the virus has been genetically modified to prevent harm to healthy cells.
Example 4: Drugs can be made from the virus: Researchers at Oncolytics Biotech Inc., of Calgary, Canada, have developed a therapeutic drug, REOLYSIN, from the same Reovirus and are conducting multicenter clinical trials for a variety of cancers. Renowned American Hospital Cedars-Sinai is one of those participating, and in this case is looking into recurrent gliomas, the most common and deadly brain cancer.
"Although not every glioma cell line has an activated Ras pathway, Ras activation is very common in these malignant brain cancers. In lab tests and animal studies, the reovirus appears to target Ras-activated tumor cells and leave normal cells alone," said a spokesperson from Cedars-Sinai.
Example 5: Dalhousie Medical School have proven that Reovirus can infect and kill breast cancer stem cells (September 2009). This breakthrough finding was published in Molecular Therapy, the journal of the American Society of Gene Therapy.
Dr Lee, head researcher said, It is only within the past few years that the scientific community has understood the full significance of cancer stem cells and the urgent need to find a means of eliminating them (Ed: Actually, UK embryologist John Beard in 1906 told the world but his work was ignored until picked up by William Kelley then Dr Gonzalez from the 1970s. Oh, but they really were Alternative Doctors!)
Cancer stem cells are essentially mother cells, explains Dr. Lee, Cameron Chair in Basic Cancer Research at Dalhousie Medical School. They continuously produce new cancer cells, aggressively forming tumours even when there are only a few of them.
Cancer stem cells are difficult to kill as they respond poorly to chemotherapy and radiation. As Dr. Lee notes, You can kill all the regular cancer cells in a tumour, but as long as there are cancer stem cells present, disease will recur. Dr. Lee is optimistic that his team has found the key to destroying cancer stem cells.
Example 6: Boston University School of Medicine (BUSM) presented their findings in the Journal of Virology on December 2010. They were using a virus, vesicular stomatitis virus (VSV), to kill cancer cells. VSV is supposedly not an important cause of ill health in humans.
In cancer cells a major signaling pathway, called the AKT signaling pathway, is frequently turned on and AKT signaling is a cell survival signal, helping to keep the cancer cells alive. VSV can switch off the AKT pathway and cause cancer cell death. VSV can also prompt the immune system to produce interferon which also targets the diseased cancer cell.
Example 7: Memorial Sloan Kettering Cancer Center in New York are now getting in on the act. As recently as May 2011, Joyce Wong M.D. published findings looking at oncolytic viruses to infect cancer cells, and especially stem cancer cells in pancreatic cancers The researchers have looked at a number of such common viruses, all modified to avoid harm to healthy cells.
Example 8: Viruses can also be genetically modified to be carriers. For example: In December 2009, (Molecular Therapy0 Ohio State University researchers looked at modifying viruses so that they carried a gene which made a protein that could block tumour blood cell formation.
Looking at brain tumours, research leader Balveen Kaur, associate professor of neurological surgery said, "This is the first study to report the effects of vasculostatin delivery into established tumors, and it supports further development of this novel virus as a possible cancer treatment," "This study shows the potential of combining an oncolytic virus with a natural blood-vessel growth inhibitor such as vasculostatin. Future studies will reveal the potential for safety and efficacy when used in combination with chemotherapy and radiation therapy," she says.
The work still needs to be trialled with humans. In this study researchers injected the cancer-killing virus, called RAMBO (for Rapid Antiangiogenesis Mediated By Oncolytic virus), directly into human glioblastoma tumors growing either under the skin or in the brains of mice.
Example 9: Professor Norman Nevin, chair of the UK gene therapy committee believes the UK is at the forefront of oncolytic virus work. For example, his committee gave the go-ahead several years ago for a team at Glasgow University (Southern General Hospital), lead by Professor Moira Brown, to treat 100 patients with gliomas using a genetically modified form of the herpes virus. Here initial findings and the development work has been covered in Cancer Watch in October 2013 (see HERE).
Our Bottom Line
(Chris Woollams) As always, we are not endorsing, writing in glowing terms, or promoting. We just call it as we see it. And clearly there is definitely something of great potential here as a cancer treatment. Hopefully this briefing, on a subject that has grown rapidly in the last few years, will help you to make more informed choices on your options for cancer treatment over the coming years, should you be offered virotherapy.
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