Aug. 6, 2002 Researchers at the University of Chicago have found a way to combine cancer chemotherapy with gene therapy designed to disrupt the growth of blood vessels to a tumor. The combination, tested in mice, is far more effective than standard chemotherapy and has no additional side effects. This innovative approach is described in the August issue of the Journal of Clinical Investigation. This new approach evolved out of a similar system, now entering phase-2 human trials, that combines gene therapy with radiation therapy.
"The radiation therapy approach appears to be quite effective, aiming a powerful anticancer arsenal at the tumor," said Ralph Weichselbaum, M.D., professor and chairman of radiation oncology at the University of Chicago and director of the study. "The new combination with chemotherapy, however, not only enables us to target the original tumor but also potentially to aim at the small clusters of cancer cells that may have spread to distant sites."
The therapy uses a modified cold virus to insert the gene for tumor necrosis factor (TNF) into cells within a tumor. TNF is a potent biological substance that can kill cancer cells directly and disrupt their blood supply, but it can be very toxic when given systemically. The researchers originally altered the TNF gene so that it could be turned on by radiation therapy. Now they have produced a version of the gene that can be activated by exposure to the common anti-cancer drug cisplatin. So mice treated with both the gene injections and cisplatin have high concentrations of TNF within the injected tumors, but nowhere else.
The researchers found that the combined therapy was far more effective than either cisplatin or TNF-gene injections alone. Tumors treated with the combination of gene therapy and cisplatin had "significant regression," note the authors, with "no additional toxicity."
Untreated tumors doubled in size within four days and grew to more than four times their original size in two weeks. Tumors treated with cisplatin alone or injected with the virus alone grew more slowly.
Cisplatin is currently used to treat many types of cancer, including lung, head and neck, ovarian and bladder cancers. Adding TNF increases the anti-cancer effects of cisplatin at the injection site. It may also interfere with the tumor's ability to increase its blood supply. Since TNF was produced only at the injection sites, it did not increase toxicity.
TNF may also, indirectly, support cisplatin's assault on distant metastases. Earlier this year Weichselbaum's group showed that TNF stimulated the production of angiostatin, which inhibits a tumor's efforts to grow new blood vessels.
This novel approach to combination cancer therapy grew out of a series of discoveries from Weichselbaum's laboratory. In 1989, they discovered that radiation therapy could induce cancer cells to release small amounts of TNF, which in turn made the radiation more effective.
In 1998, Weichselbaum showed that radiation dramatically enhanced the effects of angiogenesis inhibitors -- natural substances such as angiostatin or endostation. These interfere with a tumor's efforts to grow new blood vessels, which are necessary for tumor growth.
Since 1999, Weichselbaum has worked with colleagues and scientists at GenVec, a biotech company based in Gaithersburg, MD, to develop safe and effective ways to insert a supercharged TNF gene into tumor cells. Infected cells produce high levels of TNF only when radiation or chemotherapy turns on the gene.
This research was supported by grants from the National Cancer Institute and GenVec. Two of the authors have patented this novel approach to combination cancer therapy and have a financial interest in the the company that produces the virus.
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