Shock therapy: Electroporation moves from lab to clinical trials

West Yorkshire, England - For the first time, scientists are testing a laboratory technique for introducing genetic material in human beings. The phase 1 clinical trial of electroporation focuses on patients with metastatic melanoma.

As a gene therapy technique, electroporation is relatively simple, says Adil Daud, M.D., an assistant professor of medicine and oncology at Moffitt Cancer Center in Tampa.

"We know the genetic material is getting through," Dr. Daud says, "because we're getting an estimated 20 percent gene expression. That's very good."

The introduced genetic material, which expresses the interleukin-12 protein into tumors, functions as a trigger to the immune system, awakening it to the danger posed by melanoma cells.

Methodology

Getting genetic material into cells - and having it do what researchers want it to do –- is not an easy matter.

Using viruses as a byway is dangerous because they are difficult to control. Scientists have tested a variety of nonviral methods, such as direct injection and packing genes in liposomes, but without achieving satisfactory gene expression.

While scientists have long used electroporation in the laboratory, the general thinking was that the discomfort of electric shock precluded the technique's use in people. Taking the opposite stance, Richard Heller, Ph.D., (who helped to develop the technique) began testing electroporation on mice six years ago. Ultimately, he obtained an 80 percent cure rate. Also, he found that, when melanoma cells were reintroduced to mice in remission, the immune system again attacked the tumor, suggesting a memory mechanism. Dr. Heller is professor of microbiology at the University of South Florida.

In 2005, Dr. Daud launched a phase 1 clinical trial on stage four melanoma patients.

He says, "The mouse immune system is very different from a human's. We don't know if it will work or not. Our first goal is to see if the treatment is safe and tolerated and the gene is expressed."

Besides a stage four diagnosis, patients must have biopsy-proven metastatic melanoma, have no history of seizures or cardiac arrhythmia, and must be otherwise fit and healthy and their melanoma tumors must be close to the surface of the skin. They must also have at least two tumors that could be electroporated. They must also have normal liver function tests and kidney function tests and adequate bone marrow function.

Blood tests and biopsies are taken before treating the patient. Each patient is given genes that express interleukin-12 via electroporation on days one, five and eight. Electroporation takes place on three to 12 tumor sites per patient. Biopsies and blood tests are taken on days 11, 22 and 39.

Excellent early esults

So far, gene expression is excellent and patients are tolerating the treatment very well.

Although Dr. Daud cautions that a cause-effect relationship is not clear, he also says some tumors in some patients have shrunk.

As to whether the gene expression is localized or systemic, he says, "I don't know yet. We've done some tests but don't have the results. By June we'll have 15 to 20 patients and should know then."