The cause of one notorious childhood disease, poliovirus, could be used to treat the ongoing threat of another childhood disease, neuroblastoma. In the March 15 issue of Cancer Research, researchers from Stony Brook University report that an attenuated -- or non-virulent -- form of poliovirus is effective in obliterating neuroblastoma tumors in mice, even when the mice had been previously vaccinated against the virus.
By its nature, poliovirus destroys the cells it infects in an attempt to replicate copies of itself. When released from the cells it kills, the replicated particles then attack surrounding cells. The Stony Brook researchers took advantage of this viral property by injecting a stable, attenuated strain of poliovirus directly into neuroblastoma tumors transplanted into 12 mice engineered to contract polio. The virus was able to destroy tumors in all 12 mice; however tumors reoccurred in two mice by the end of the 180-day study period.
None of the mice experienced any ill effects from the virus itself. According to the researchers, any viral particles that make it to the bloodstream would be destroyed by antibodies created through poliovirus vaccination. The researchers believe that their findings, if developed to work in humans, could represent a safe, practical means of treating a deadly childhood cancer and possibly many other cancers in adults.
"A tamed poliovirus represents a significant step in finding viral treatments that can kill tumors without harming patients," said Hidemi Toyoda, M.D., Ph.D., a pediatrician and postdoctoral research fellow in Stony Brook's Department of Molecular Genetics and Microbiology. "Effectively, we have harnessed a virus that was deadly in children just a few decades ago, namely polio, and used an essential aspect of its nature to destroy a disease that is deadly today."
Surprisingly, the researchers also discovered that the poliovirus treatment effectively protected the mice against new tumor growth, a significant factor when fighting a disease like neuroblastoma, which is known to reoccur following chemotherapy.
Neuroblastoma is the most common form of solid tumor in children. It is a cancer of the sympathetic nervous system, the network of nerves that regulate unconscious body activities such as breathing. The cancer most often occurs as a mass or lump on the adrenal glands, which are located on top of the kidneys.
While chemotherapy and radiation therapy are generally effective for some cases of the disease, the prognosis is poor for children with high-risk neuroblastoma.
"Neuroblastoma can be very difficult to treat and the chemotherapies used can lead to health problems later in life," Toyoda said. "In combination with conventional therapy, a poliovirus treatment could reduce the exposure of a child to chemotherapy or radiation and lower the risk of harmful side effects."
To test the effectiveness of poliovirus against cancer tissue, the researchers first had to develop a safe form of the virus. Toyoda and his colleagues work in the laboratory of Stony Brook professor Eckard Wimmer, Ph.D., who in 2002 synthesized poliovirus from its basic chemical components. Based on the properties of the synthetic poliovirus, Wimmer created the highly attenuated virus used in this study by substituting a single nucleotide, located in a functionally important portion of the viral RNA genome called a "spacer region", with an essential regulatory gene removed from elsewhere in the viral genome.
According to Jeronimo Cello, Ph.D., senior author of the Cancer Research paper and research assistant professor at Stony Brook, this engineering feat is like putting a double failsafe into the virus.
"The engineered poliovirus cannot produce neurovirulent copies of itself if the spacer region remains interrupted," said Cello. "And in the unlikely event that the regulatory gene element is deleted, the virus would not be able to reproduce."
To test the virus' ability to destroy neuroblastoma the researchers constructed a transgenic mouse model that allows growth of neuroblastoma cells and carries the human gene for CD155, which codes for the receptor that allows poliovirus to enter cells. The mice were then vaccinated against poliovirus.
Since most humans are immunized against poliovirus, Toyoda and his colleagues needed to know whether such immunization would interfere with the use of the virus in tumor therapy. By injecting the virus directly into the mouse tumors, the researchers demonstrated that it was possible to reach their target and still avoid interacting with the anti-poliovirus antibodies generated by the vaccine.
Not only did the poliovirus prove effective in destroying the tumors, the treatment with virus also seemed to prevent tumors from recurring. Subsequent transplanted tumors were also destroyed, presumably through an enhancement of anti-tumor immune response, say researchers. Since the poliovirus was gone from the system, however, the researchers are unsure of exactly how that immune response occurred.
"This immunity against neuroblastoma acquired by the animals is still something of a mystery, one that we hope to address in future studies," Toyoda said. "But it is an encouraging sign since neuroblastoma are known to relapse quite frequently."
The study was funded by the National Institute of Allergy and Infectious Diseases and the Stony Brook Sunrise Fund for Pediatric Cancer.
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