Emory Researchers Advance Gene Therapy Studies For Metastatic Melanoma Treatment

April 24, 1997

Melanoma researchers at Emory University's Winship Cancer Center are uncovering new information about a vital cellular ingredient which they believe may direct the body's immune system to kill malignant melanoma tumor cells, the most dangerous, and potentially deadly, type of skin cancer.

If large doses of this ingredient can be delivered to melanoma tumors directly, the researchers believe it might be used to effectively treat advanced cases of melanoma.

In gene studies on melanoma tumors, Emory researchers John Ansel, M.D., and Cheryl Armstrong, M.D., have discovered that a cytokine called GM-CSF (granulocyte macrophage colony stimulating factor) directs the immune system to shift into overdrive and attack melanoma tumor cells. Cytokines are natural proteins made by all cells, both normal and malignant. A single cell produces many cytokines; some influence the cell itself (an autocine effect), while others stimulate neighboring tissue, such as immune cells, for a local effect. GM-CSF is produced naturally by some human melanoma tumors, but in amounts too small to effectively eliminate tumors.

"In mouse studies, we tried delivering GM-CSF in large doses, directly to the tumor," explains Dr. Ansel. "We grew melanoma tumor cells in culture and added the GM-CSF gene. Then we reinjected the combination back into the mouse."

It worked. The animal grew a tumor that produced an abundance of the cytokine locally. It took just five days to completely eliminate tumor cells in more than half of the mice. The other half still developed tumors, but they shrank by at least 90 percent, compared with tumors not treated with the GM-CSF gene.

"Our next step is to mimic the human condition even more closely," says Dr. Armstrong. "We are developing cell lines that will metastasize in the mouse just like you'd see in a human. Then we will inject the GM-CSF gene directly into the established tumor in the mouse to see if it generates enough GM-CSF to stimulate the mouse to mount a heightened immune response and destroy the tumor."

"In our studies, positioning the GM-CSF in direct contact with the melanoma cells could make a big difference," adds Ansel. "It may pack a much bigger punch than when it is coursing through the circulatory system."

Most clinical gene therapy for melanoma now being conducted around the country treats patients systemically, and results have not been particularly promising.

"We are experimenting not only with injecting the gene directly into the tumor," says Dr. Armstrong, "but also injecting the actual cytokine itself."

The presence of cytokines such as GM-CSF may eventually provide valuable prognostic indicators for melanoma that could improve treatment. The trick is to determine which cytokines actually combat tumor enlargement and which ones create a fertile environment in which the tumor fluorishes. The presence of certain cytokines may indicate that a tumor is indeed fast-growing, calling for a more aggressive therapy than might a more gradual growth.

For example, Drs. Ansel and Armstrong have recently completed a study using pathology archives to contrast the thickness of melanoma tumors. The researchers found that those tumors which produced GM-CSF were all thinner than those tumors which produced the cytokine IL8, which is known in many melanomas to be an autocrine growth factor.

Eventually Winship Cancer Center scientists plan to devise an entire menu of cytokine cell markers that would act as a road map for tumor behavior. They hope that the markers might also indicate how the tumors would react to different therapies. The significant number of studies currently underway throughout the country on cytokine markers makes this a realistic goal for the near future.

Drs. Ansel and Armstrong and their colleagues in Emory's Melanoma and Pigmented Lesion Center are developing a new protocol using GM-CSF to treat patients with advanced melanoma in the very near future.

"The most effective strategies for treating melanoma may well turn out to be those that combine several cytokines in parallel, or cytokines combined with chemotherapy," Dr. Armstrong notes.
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Emory University Health Sciences Center

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