Mouse research indicates that a new therapeutic approach employing an oncolytic virus may be effective against malignant glioma, according to an article in the May 7th issue of the Journal of the National Cancer Institute.

The therapy, known as Delta-24-RGD, may be the first effective treatment for malignant glioma, the most lethal form of brain cancer. The technique involves a replication-competent adenovirus that can spread throughout a tumor showing oncolytic activity (that is, it infects and destroys cancer cells).

The findings are considered so promising that the National Cancer Institute is providing financial support for its laboratories to produce a drug-grade version to test in humans, possibly by late 2004. "We believe this therapy has a lot of potential, but one that needs much more study," said lead author Juan Fueyo, M.D. "We've never seen this kind of response before with any other treatment tested in either animals or humans."

The Delta-24-RGD virus replicates only in cancer cells, not in healthy cells, and replication results in death of the host cancer cell. When no more cancer cells remain to infect, the virus itself dies.

"Biologic viral therapy like this may be just what we need to treat a complex disease like cancer," said Frederick Lang, M.D., a primary investigator of the study. "Cancer can be devious in that it does everything possible to evade destruction. But viruses are equally tricky in their quest to invade cells and propagate. In this experimental war between cancer and a viral therapy, the virus won. Of course, we hope to obtain similar results when patients are tested, but we cannot predict such success based on animal studies."

The international team found in repeated experiments that more than half of the mice that had human glioblastoma cells implanted in their brains and treated with Delta-24-RGD survived for more than 4 months, whereas untreated mice lived for less than 3 weeks. The mice were considered clinically cured of their brain tumors. On necropsy, investigators found only empty cavities and scar tissue where the tumors had been.

Recent advances in the understanding of brain tumor biology led researchers to target molecular defects in brain tumors. The research team behind the current study focused on a gene and protein product that malfunctions in nearly all malignant gliomas as well as in many other solid tumors ---- the retinoblastoma protein. The protein prevents certain other regulatory proteins from triggering DNA replication. If it is missing or nonfunctional, a cell can replicate over and over, resulting in carcinogenesis.

In normal cells, the protein also prevents a virus that enters a cell from replicating. However, adenoviruses express a protein known as E1A that binds to the retinoblastoma protein and inhibits its function. During typical infection, that binding action allows the virus to spread to additional cells.

The Delta-24-RGD therapy takes advantage of the mutant retinoblastoma protein in cancer cells by introducing a virus with a non-functioning E1A protein. Investigators created the new virus with a 24-base pair deletion in the adenovirus E1A gene so that the malfunctioning E1A protein cannot stop the retinoblastoma protein from functioning. Thus, the virus can infect and kill only cancer cells. A healthy cell with a normal protein can successfully defend itself against the virus.

Mice in each experiment were divided into 3 groups of 6 to 10 animals and all received injections directly into the brain tumors. The mean survival time for mice in the control group, which received a placebo, was 19 days. Of 26 mice treated with Delta-24 therapy, 4 (15 percent) were considered cured because they survived for more than 4 months, or to the end of the experiment. In addition, 15 of 25 (60 percent) mice that received Delta-24-RGD were symptom-free, long-term survivors. Although researchers do not know why some mice treated with Delta-24-RGD did not survive, they theorize that, due to natural variation, some animals may have needed a bigger dose of the therapy.

The researchers do not know if the human immune system will act against the virus. "We hope that an immune reaction will not inactivate the therapeutic virus," Lang said. "We want to get to the tumor before the virus can be inactivated."