The Basics about Oncolytic Viruses
A press release issued by the Ottawa Hospital Research Institute in Ottawa, Ontario, Canada, on May 20, 2010, reported that Phase 1 clinical trials conducted conjunctively in Ottawa and three American cities has resulted in a huge step forward for oncolytic therapy in fighting cancer.
The term "oncolytic" actually means cancer killing (onco - cancer; lytic - killing). Oncolytic viruses are microorganisms that have been selected or engineered to grow inside tumor cells. As the tumor evolves, mutations in multiple genes contribute to the growth of the tumor. Oncolytic viruses target cancer cells and exploit the cells' ability to grow and spread.
Researchers have been able to genetically alter these viruses to do one of three things:
1) to take advantage of tumor-specific mutations in the cancer cells' antivirus defenses;
2) to feed off a tumor's signals or programs that would normally allow the cancer cells to grow or spread;
3) to restrict the spread of cancer cells into healthy cells based on antibody generators that are specialized or overexpressed on the surface of the tumor cells (www.medscape.com).
In other words, "viruses have been engineered to take advantage of specific tumor associated molecular changes" (http://oncolyticvirus.wordpress.com). These viruses are usually non-human in origin since the human body will not have built up immunity to these viruses. Clinical studies have shown that these cancer-killing viruses have a higher ratio of toxic dose to therapeutic dose - that means that more of the virus can be tolerated by a patient before the virus actually becomes toxic. Most oncolytic viruses have an index of 100,000:1. By contrast, chemotherapy is much more toxic at 6:1.
Initial human trials using oncolytic viruses (also known as virotherapy) generated a lot of excitement but yielded tumor regression that was followed by tumor progression in the later stages of the trials. As research into these viruses and cancer cells have continued, researchers and scientists have learned how to further manipulate the viruses to enhance results.
The Latest Canadian/U.S. Oncolytic Virus Trials
Rb/p16 is an example of a cancer-killing virus that has been studied. It was so-named because Rb/p16 is a central growth circuit in cancer cells that is usually defective. So this particular virus halts the progress and eventually kills the cancer by preventing it from reproducing and spreading.
VSV (vesicular stomatitis virus) is a mild, non-fatal disease found in cattle and pigs. It is extremely sensitive to the antiviral response of its host - which is defective in cancer cells. Humans do not develop the symptoms of the virus that would normally appear in animals.
The most recent trial held in Ottawa, Canada, and three American cities was with the virus JX-594. Dr. John Bell and his colleagues at the Ottawa Hospital Research Institute (OHRI) have been developing oncolytic viruses for nearly a decade. The purpose of the trials was to directly inject the virus in varying doses into the bloodstream of patients with a variety of cancers. Researchers then monitored the tumor responses.
The study was sponsored by Jennerex Therapeutics of San Francisco.
The results of Phase 1 of the study were presented to the American Society of Gene and Cell Therapy (ASGCT) Annual Meeting in Washington, DC.
This is the first clinical trial that involved injecting the virus into the bloodstream. Being able to inject the virus means that doctors can now target cancer cells throughout the body. Previous clinical trials have involved injecting the viruses directly into the tumors.
The patients chosen to participate each had various types of solid tumors that hadn't responded to previous treatment attempts. Biopsies showed that the virus had actually reached and replicated inside the tumor, and had destroyed tumor tissue in six patients who received the higher doses, with those patients reporting flu-like side-effects.
About the JX-594 Virus
JX-594 is a member of the poxvirus family, derived from the vaccinia virus strain that has been used in the smallpox vaccine. Researchers discovered that this virus naturally replicated in certain cancer cells. The clinical trials were initiated to find out which cancer cells and at what doses is the virus effective (www.ohri.ca).
"'These data represent a significant milestone for the field of oncology and viral therapy as this is the first time that a viral or genetic product has demonstrated reproducible, biopsy-proven delivery to multiple solid tumor types following intravenous administration'" (David H. Kirn, M.D., president and chief executive officer of Jennerex.
"'JX-594 represents a promising potential treatment option for patients with multiple types of cancer. As the first intravenous biological immunotherapy to demonstrate safety and tumor-specific delivery, JX-594 may add significantly to the armamentarium for many solid tumors'" (Andrew R. Haas, M.D., Ph.D., Hospital of the University of Pennsylvania).
Sources: www.medscape.com; http://oncolyticrivurs.wordpress.com; www.jennerex.com; www.mcgill.ca; www.ohri.ca