Researchers discover how cyclophosphamide chemotherapy drug helps a cancer-killing virus

Aug 31 2006

Researchers here have discovered how a specific chemotherapy drug helps a cancer-killing virus. The virus is being tested in animals for the treatment of incurable human brain tumors.

The virus, a modified herpes simplex virus, is injected directly into the tumor, where it enters only the cancer cells and kills them. The study found, however, that within hours of the injection, infection-fighting immune cells are drawn into the tumor to attack the virus, reducing the treatment's effectiveness.

They also found that a chemotherapeutic drug called cyclophosphamide briefly weakens those immune cells, giving the anti-cancer virus an opportunity to spread more completely through the tumor and kill more cancer cells.

Specifically, the drug slows the activity of immune cells called natural killer (NK) cells and macrophages, which are the body's first line of defense against infections.

The virus and drug cannot be used yet in humans because they require further study, as well as testing for safety and effectiveness through the clinical trials process.

The research, led by investigators with the Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, is published in the Aug. 22 issue of the Proceedings of the National Academy of Sciences.

"Our findings suggest that we can use this drug to limit the action of these early responding immune cells, giving the virus time to grow and destroy the tumor," says study leader E. Antonio Chiocca, professor and chair of neurological surgery and director of OSU's Dardinger center for neuro-oncology.

"They also suggest that the drug may allow us to temporarily inhibit just this early immune response, making it unnecessary to totally suppress the immune system when using this treatment."

In the late 1990s, a student of Chiocca's discovered that the virus killed tumors more effectively when the animals were first given the drug. Chiocca then set out to learn why.

In this study, one of Chiocca's fellows, Giulia Fulci, now at Massachusetts General Hospital in Boston , examined brains from rats treated with the virus, with and without the drug to identify the immune cells present in the tumor before injection of the virus, and at different times afterward.

Six hours after the injection of the virus, she found that high numbers of NK cells, macrophages and brain-tissue immune cells called microglia had moved into the tumor. The number of macrophages, for example, had risen three fold. In animals given the drug, on the other hand, the number of these immune cells increased by only one half.

Other experiments performed together with Michael A. Caligiuri, director of the OSU Comprehensive Cancer Center , revealed that when the drug is added to NK cells growing in the laboratory, the cells stop making an immune substance called interferon gamma (IFNg). One key effect of IFNg is to attract immune cells to an infection site. The production of the substance could therefore intensify the immune response against the anti-cancer virus.

Furthermore the researchers found that in rat brain tumors treated with the virus but not with the drug, IFNg levels rose by 10 times after six hours and by more than 120 times after 72 hours. Animals given the drug showed only small increases of IFNg.

Lastly, the researchers tested the treatment in brain tumors in mice that cannot make IFNg. They found that viral genes were expressed much more in these animals.

Overall, the study suggests that cyclophosphamide improves the cancer-killing ability of this virus by inhibiting the activity of NK cells and certain other immune cells and by blocking the ability of cells to make IFNg.

"Over the past decade, cancer-killing viruses have been tested in people as a treatment for cancers of the pancreas and lung, as well as brain tumors, and the viruses have proven to be fairly safe," Chiocca says.

"One reason these viruses have been so safe may be that they have been so weakened, or attenuated, that they now need help once they are inside tumor cells. One way to help them is to limit the ability of the immune cells that are the body's first line of defense against the virus, perhaps by using this drug."