Study Raises Prospect Of Practical Vaccine For Metastatic Melanoma

Writing in the Sept. 1 issue of the Journal of Clinical Oncology, investigators led by Dana-Farber's Glenn Dranoff, M.D., report that the vaccine, made by inserting a key gene into a patient's own melanoma cells, prompted a powerful immune system attack on melanoma tumors in several patients who received it in a clinical trial. More than three years after the trial began, 10 of the 35 patients who initially enrolled were still alive, and four of them had no signs of disease.

These results, which are comparable to those obtained by Dranoff and his colleagues in earlier studies of similar, but harder-to-work-with vaccines, suggest the technique holds real promise as a useful treatment for metastatic (spreading) melanoma.

"Our findings show that an antitumor immune response to melanoma can be created using a vaccine that is safe and relatively easy to make," says Dranoff, the study's senior author. "The survival of 10 patients for more than three years is especially encouraging and raises the possibility that vaccination might be effective in combination with other, existing therapies."

Like all vaccines, the one developed by Dranoff and his colleagues seeks to intensify the body's normal immune-system attack on diseased cells. It is based on the idea that melanoma cells, which are normally camouflaged from the immune system, can be made to betray their presence in the body, sparking an especially vigorous immune response.

The vaccine is made by removing a portion of a patient's tumor and mixing it with specially equipped viruses, which carry a gene for a substance called granulocyte-macrophage colony-stimulating factor (GM-CSF). The viruses invade the melanoma cells and deposit the gene there, causing the cells to begin pumping out GM-CSF. The cells are then re-injected into the patient.

GM-CSF acts like a magnet for agents of the immune system, drawing an attack on melanoma cells throughout the body, not just those that contain the GM-CSF gene. When tumor samples from vaccinated patients are viewed under a microscope, cancer-fighting cells are often found swarming around the melanoma cells – evidence of a potent immune response.

When the technique was first tested in melanoma patients, Dranoff and his colleagues used a retrovirus (whose genetic programming is written in RNA rather than DNA) as the delivery vehicle for GM-CSF. While the results were encouraging, the process of preparing the vaccine was both lengthy and cumbersome. The retrovirus enters only cells that are actively dividing and could itself increase the risk of cancer. Vaccines prepared in this fashion therefore require extensive safety testing before being injected into patients.

The vaccine used in the new study, by contrast, was made with a weakened cold virus, known as an adenovirus, as the gene-ferrying agent. Adenoviruses are capable of entering resting cells and produce fewer complications than retroviruses.

The study, a Phase I trial undertaken to assess the vaccine's safety and potential effectiveness, involved 35 patients with metastatic melanoma, a type of cancer that begins in the skin but which, if spread to other parts of the body, carries a high death rate. Vaccines were successfully made for all but one of the patients. Eight patients had to withdraw from the study because their disease progressed rapidly. Side effects of the treatment were generally minimal, usually amounting to no more than irritation around the injection site.

Researchers removed tumor samples from 16 patients following vaccination to gauge the extent of the tumor response. In 10 of those cases, they found a large influx of immune system cells and substantial numbers of dead melanoma cells. Plus, ten of patients – 29 percent of the original group – were alive three years after receiving the treatment.

The results have encouraged Dranoff and his colleagues to undertake a larger, Phase II study of the vaccine and to test whether it can be effective in patients whose melanoma has not yet spread systematically.

"We plan to explore alternative techniques for producing the vaccine, as well as determining which patients can benefit from it the most," Dranoff remarks. "This will help us determine its proper place in the arsenal of melanoma treatments."

Co-authors of the study include Dana-Farber researchers Robert Soiffer, M.D., and Stephen Hodi, M.D.; Frank Haluska, MD, PhD, and Martin Mihm, MD, of Massachusetts General Hospital; and colleagues at Brigham and Women's Hospital, Harvard Medical School, Beth Israel Deaconess Medical Center, Children's Hospital Boston, and Cell Genesys of Foster City, Calif.

The study was funded in part by the National Institutes of Health, the Cancer Research Institute, the Leukemia and Lymphoma Society, and Cell Genesys.

Dana-Farber Cancer Institute is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.