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DNA Vaccine Starves Tumors in Mice
By Nancy Touchette

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In trying to develop new therapies to fight cancer, researchers are constantly frustrated by tumor cells' uncanny ability to mutate and become resistant to the anticancer drugs designed to kill them.

Staining of metastatic lung tumors treated with DNA vaccine reveals an attack of T cells (stained green) on tumor blood vessels (stained red).

Because tumors require a supply of blood to continue to grow and spread, some researchers have tried to combat cancer by cutting off the blood supply to the tumor rather than killing the cancer cells directly. This approach requires relatively high doses of drugs designed to inhibit the growth of blood vessels and so far no successful therapies have emerged from clinical trials in humans.

Now, a new study in mice is breathing new hope into the idea of treating cancer by eliminating a tumor's blood supply. The new approach enlists the help of the immune system to target and kill tumor blood vessel cells.

Ralph A. Reisfeld and his colleagues at the Scripps Research Institute in La Jolla, California, have developed a novel DNA vaccine that stimulates a type of immune cell, the T-cell, to seek out and destroy the blood vessels that feed growing tumors in mice. The vaccine protected mice against melanoma, colon cancer, and lung cancer.

"Virtually all vaccine work done to date has targeted the tumor," says Jeffrey Schlom, who heads the Laboratory of Tumor Immunology and Biology at the National Cancer Institute in Bethesda, Maryland. "This new study marries the fields of DNA vaccines and anti-angiogenesis by targeting something in the vasculature. It's ingenious in its conception."

Schlom cautions, however, that the work is preliminary and many more studies are needed before a vaccine is ready for use in humans. The current findings are reported in Nature Medicine.

"This is a novel strategy," says David Cheresh, who studies angiogenesis inhibitors at Scripps."Through an unprecedented recruitment of the immune system, they were able to generate a strong anti-tumor effect by targeting the central component of what tumors need most—a blood supply."

A cancer cell needs access to the bloodstream to spread, or metastasize to other parts of the body. To accomplish this, it sends out biochemical signals that activate a cascade of genes that ultimately cause the growth of new blood vessels that infiltrate the tumor, in a process known as angiogenesis.

Tumor angiogenesis. View larger

To circumvent known problems in using DNA as a vaccine, Reisfeld and his colleagues engineered bacteria to deliver the gene to mice. They modified Salmonella typhimurium bacteria to express a gene for a protein produced in tumor blood vessels but not in normal blood vessels. The protein, called the VEGF receptor, acts as an antigen to trigger an immune response in mice.

As a result, an army of killer T cells specific for the VEGF receptor proliferates and attacks the tumor blood vessels, stopping them dead in their tracks and effectively choking the blood supply to the tumor. Deprived of nutrients, the tumor starves to death.

The vaccine prevented tumor growth in mice in the short term and the long term. The researchers injected melanoma or lung cancer cells in mice two weeks after their vaccination and the animals had much less tumor growth than un-vaccinated mice. Animals injected with colon cancer cells were protected against disease up to ten months after vaccination.

The researchers also found a reduction in metastasis in vaccinated animals. The vaccine was effective both in preventing cancer cells from growing and in shrinking tumors that were already established.

Reisfeld predicts that DNA anti-angiogenesis vaccines could be effective in preventing metastases and cancer recurrence. "Using traditional cancer therapies, many people are temporarily cured, but frequently the tumor comes back," says Reisfeld. "We hope that this approach could slow down or even prevent a recurring disease."

This type of vaccine might be most effective when used in combination with therapies that directly target the cancer cell, he says.

"The beauty of this work is that it could potentially work against many types of tumor cells," says Cheresh. Because the vaccine targets the blood vessels, one vaccine could be effective in treating different types of cancers. Potentially, the use of vaccine as therapy to treat cancer could have several advantages over conventional therapies that directly target tumors.

Chemotherapeutic drugs are by their nature, toxic, and cause harmful side effects. But a vaccine enlists the help of the immune system to mount an attack against blood vessels recruited by the tumor. Even after the initial attack, a small population of T cells remains in the bloodstream and can be triggered at any time the need arises.

Staining of metastastic lung cancer cells shows a reduction in blood vessels in mice treated with vaccine (right) compared to unvaccinated mice (left). View full

"T cells are killer cells that have a memory," says Reisfeld. "A vaccine is effective only if it has a memory."

The researchers are using DNA microarray analysis to find other potential vaccine targets to develop even more effective and selective DNA vaccines. They are particularly interested in identifying genes that are turned on in blood vessels recruited by the tumor, but not in normal vessels.

"We don't need to understand the function of a gene for it to be a good vaccine candidate," says Andreas G. Niethammer, a colleague of Reisfeld's at Scripps. "All we need is to find a gene expressed, or turned on, in the tumor blood vessels, but not in normal blood vessels. Once we have that target, the tumor blood vessels can be destroyed by the immune system."

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Niethammer, A.G. et al. A DNA vaccine against VEGF receptor 2 prevents effective angiogenesis and inhibits tumor growth. Nat Med Published online November 4, 2002.
Hood, J.D. et al. Tumor regression by targeted gene delivery to the neovasculature. Science, 296, 2404-2407 (June 28, 2002).
St. Croix, B. et al. Genes expressed in human tumor endothelium. Science 289, 1197-2102 (August 18, 2000).

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