Foes Turn Allies In Cancer Battle

Polio and common cold viruses can be 
used to tame brain tumors, Biplab Das explains 

Researchers at the Duke Comprehensive Cancer Centre of the Duke University, North Carolina, have produced a cocktail of polio and common cold viruses, which has destroyed deadly brain tumours within four to six hours. The cocktail has wiped out cancer cells in laboratory cell cultures and in animals. The virus spared the normal brain cells while killing cancer cells derived from primary brain tumours as well as cells derived from breast and colon cancer. 

"We made a drug out of a virus by engineering its destructive abilities, converting it a friend from a foe," said Dr. Matthias Gromeier, professor of molecular genetics and microbiology who led the Duke team. "The brain is a very common site of cancer, but cancer in the brain is extremely difficult to treat. Our treatment is directed against the most common and lethal type of brain tumour - malignant glioma," he said in an e-mail interview. "To be precise, we are targeting the most aggressive and elusive form of glioma, known as glioblastoma multiforme." 

It accounts for 30 per cent of all brain tumours which originate from the brain's supporting cells, called glial cells. These tumours have tentacle-like cells that quickly invade the surrounding tissue. "Our research has identified this type of tumour as the most susceptible to our treatment. However, our treatment does not exclude other types of brain tumours as suitable targets," Gromeier said. 

The brain is separated from the rest of the body by a blood-brain barrier that keeps out foreign particles. Tumours of the brain never spread beyond its boundaries. "Existing chemotherapy does not cross the blood-brain barrier, so getting a drug to the target site is a huge problem," said Gromeier. "Viruses solve this problem as they can be directly injected into the tumour."

After entering the brain, the virus evades detection by the body's immune system which seeks out and destroys cancer cells. In people who have been vaccinated against polio, the immune system's soldier cells (antibodies) would battle out the polio virus because they have built up cells against the disease. But blood-brain barrier stops the soldier cells from entering the brain. Taking advantage of this, the modified polio virus kills the cancer cells in the brain. 

"In almost all of us (even though we are vaccinated) immunity to polio does not extend to the brain," Gromeier said. "This opens a window of opportunity by directly injecting the virus into the brain." 

The Duke team chose the polio virus for its natural affinity for brain cells. The virus is notorious for its ability to infect and cripple brain cells and causing poliomyelitis, sometimes even death. The team robbed the polio virus of its ability to kill normal brain cells while retaining its ability to mop up cancer cells. At first, the team tamed the polio virus by removing a small genetic element called internal ribosomal entry site (IRES), which makes the virus attack normal brain cells. Then the researchers inserted the same genetic element from common cold 'rhinovirus' into the polio virus, making it deadly for cancer cells. The rhinovirus causes common cold but doesn't infect nerve cells. 

In brain tumours, the cancer cells grow indefinitely and affect all parts of the brain. These renegade cancer cells provide an ideal breeding ground for viruses. The genetic element borrowed from the common cold virus triggers the killing spree of a polio virus, annihilating the cancer cells within a few hours. The Duke team has already achieved success in experiments with mice and primates. 

When the hybrid polio virus attacks cancer cells, it binds to cell receptor called CD155, a big protein molecule that sits on the membrane of cancer cells. CD155 is an excellent target for the prowling virus. The Duke team genetically modified mice to produce CD155 in specific nerve cells. Then they implanted CD155-producing malignant tumours into mice and injected the hybrid virus into the animals' spinal fluid. A single dose of the virus shrank the tumours within seven days. After eight days, the tumours were undetectable. 

As mice do not naturally produce CD155, the team assessed the safety of the virus by infecting 14 primates with it. Like humans, primates produce CD155 during embryonic development. "When treated with the hybrid virus, none of the primates showed any signs of weakness or other symptoms associated with poliomyelitis," said Gromeier. "Though we are yet to start human trials, we have analysed 20 human cases of brain tumours with high levels of CD155 expression." The modified poliovirus also entered the normal nerve cells but it could not grow in normal cells. Theoretically, it has long been predicted that viral therapy can terminate cancer cells. But only recently has it moved to the realm of application. 

Studies have shown that surgery, radiation therapy, steroids and chemotherapy can prolong the survival of patients with brain tumours. But most die within a year. Only about 5.5 per cent of all patients live up to five years. Primary brain tumours are actually many tumours in one (sometimes over a thousand). Each tumour has different sensitivity to anti-tumour treatments. Blood supply to the tumour is quite peripheral, surrounding rather than entering it. 

The centre of the tumour contains living cells in low oxygen and this makes them virtually impregnable to chemotherapy, radiation therapy and immunotherapy. Even removing 99 per cent of brain tumours by surgery leaves a billion tumour cells, which grow back in weeks or months. So the search for a viral therapy is particularly urgent for primary malignant tumours of the central nervous system.