Cancer-Killing Virus Looks Promising

In March, the television news show 60 Minutes devoted a segment to a clinical trial using polio virus to treat glioblastoma multiforme. The segment called "Killing Cancer" did a good job of illustrating the potential power of this new treatment as well as the problems associated with glioblastoma multiforme which typically kills patients in a matter of months. The CBS piece chronicled three patients whose tumors vanished after being treated with a genetically altered polio virus.

It has been known for 100 years that certain viruses can cause cancer in animals. These cancer producing viruses are called oncoviruses. In 1908, researchers in Copenhagen demonstrated that avian sarcoma virus grown in culture could be transmitted to chickens and cause leukemia. In the 1950s, it became known that viruses could remove and incorporate genes and genetic material into cells. In 1964, the first human oncovirus was isolated from Burkitt’s lymphoma cells.

This virus, Epstein Barr Virus (EBV) is now known to cause Burkitt’s lymphoma. EBV is found in all parts of the world and has 2 important strains, EBV1 and EBV2. EBV2 is more prevalent in Sub-Sahara Africa, tends to infect children at an earlier age, and can cause lymphoma in adolescents. On the other hand, HBV1 is more prevalent in developed countries, occurs in older children and teenagers and causes mononucleosis and not Burkitt's lymphoma. One interesting aside is that having exposure to malaria increases the risk of having lymphoma in children infected with EBV2.

Human papilloma virus can cause cervical cancer, HIV virus can cause a variety cancers, and hepatitis B and C causes liver cancer. Over the years, several more oncoviruses have been identified. It is estimated that seven such viruses cause 20% of all human cancers. Viruses are second only to tobacco as an identifiable cause of cancer.

The majority of viruses that cause infections do not cause cancer in humans probably because of the co-evolution of humans and viruses. In most viruses DNA is transcribed into RNA and then RNA is translated into a protein through protein synthesis. These viruses don’t incorporate their genome into the host genetic code. As a result they are eventually destroyed by cellular immunity. Some viruses behave differently, such as adenovirus an RNA virus that stores its nucleic acid in the form of mRNA and then targets a host cell as an obligate parasite. Once inside the host cell the virus transcribes differently than most viruses. The cancer-producing virus uses its own reverse transcriptase enzyme to produce DNA from the RNA genome. That DNA gets incorporated into the host cell's genome by a complicated enzymatic reaction and changes the host genetic makeup. The effect may directly cause tumors or may activate an existing ontogeny in the host cell.

This news is not all bad, however. It is possible to exploit the tendency of some viruses to do this by genetic engineering which renders the virus incapable of causing infection but allowing it to penetrate the tumor cell.

For the past 10 years, researchers at Duke Comprehensive Cancer Center have been studying the use of polio virus to treat tumors. It is well known that certain type of cancer cells have on their surface receptors which have an affinity to bind polio virus. The receptor called PVR or 155cn apparently is produced by a human gene, but is over expressed in certain cancer cells like brain tumors, certain colon cancer and in lymphoma. These receptors bind the poliovirus avidly.

In 1996, at the National Academy of Sciences Matthias Gromeier, MD, PhD, professor of neurosurgery, molecular genetics, and microbiology and colleagues replaced a segment of polio virus with a piece from a human rhinovirus, the type that causes the common cold. They named it PVS-RIPO. The engineered polio virus maintained its affinity for the receptor of cancer cells but did not cause polio. By using the right amount of recombinant virus researchers could selectively kill glioblastoma cells in cell culture without affecting normal neural cells. The virus kills cancer in two ways. The first effect occurs when the engineered virus pierces the protective shield surrounding cancer cells and produces proteins that cause the cell to burst (oncolysis). The second more important mechanism may be that the virus triggers an immune response allowing the host immunity to kill the cells with polio receptor.

Glioblastoma cells are rich in PVR receptors and the tumor is nearly always lethal. Current chemotherapy cannot adequately attack the tumor, and surgical and radiation treatments have extremely high recurrence rates. This made glioblastoma an ideal tumor to target for therapy with the newly created virus. (The CBS piece referred to this transformed virus as being Frankenstein-like, which to me understates the importance of this medical breakthrough.).

Duke researchers took this next step after painstakingly proving that the transformed virus was safe in animals. One hurdle they encountered was using cholesterol obtained from cattle to help the cell culture develop. The FDA was worried about mad cow disease and that took several years to sort out. Finally in 2010, they began a Phase 1 trial in humans to see what dose of virus would be tolerated by human patients. They began infusing small amounts of the virus into glioblastoma tumors in patients who had failed conventional treatment. They injected the virus directly in the tumor through a catheter inserted by a scope and guided by 3-D imaging. In a few cases there was a remarkable reduction in the size of the glioblastoma. They have subsequently treated 22 patients, 11 of whom have died from their disease. The treatment was able to drastically shrink the tumor size in some of the patients and completely eradicated it in the 3 patients chronicled in the 60 minutes piece.

The Duke scientists were careful not to call this a cure, but were optimistic that this could be a real breakthrough in cancer treatment. The CBS piece makes it clear that these are only Phase 1 trials, being conducted to study the safety of the treatment at the proper dose. It will years before this translates into a therapeutic tool, if it ever does, but it looks like it is an important breakthrough.