ODU's Heller Among Scientists Reporting Success Using Electroporation Gene Transfer Against Human Melanoma
A team of scientists including Richard Heller, the director of Old Dominion University's Frank Reidy Research Center for Bioelectics, has reported safe and effective treatment of skin cancer in the first ever human trial of a gene-transfer process assisted by short pulses of electricity.
The findings, published online Nov. 24 by the Journal of Clinical Oncology, show not only regression of treated melanoma skin lesions, but also an intriguing secondary effect of in vivo DNA electroporation that in some patients brought about regression of so-called "distant lesions" that had not been treated. This implies a systemic immunological response in the human body to the localized gene transfer.
The study was conducted at the H. Lee Moffitt Cancer Center and Research Institute in Tampa and the University of South Florida College of Medicine, where Heller worked before coming to ODU in July 2008 to direct the Reidy Center. He is a professor in the School of Medical Laboratory and Radiation Sciences of ODU's College of Health Sciences.
Heller and his wife, Loree, who also moved from the USF College of Medicine to ODU, are pioneers in electrogenetherapy. Their expertise promises to advance the Reidy Center's research in cancer therapies that utilize ultrashort pulses of electricity.
In electroporation, the pulses produce temporary openings in the membranes of live cells, such as tumor cells, allowing the delivery of molecular material into cells. The deliveries could be of genetic material or drugs, both of which can serve as pinpoint applications of therapies against cancer or other maladies. This procedure allows tumors to be targeted for treatment without the broad damage to healthy tissue caused by most chemotherapies today.
The Moffitt Center human trial of "electroporation-mediated gene transfer" involved 24 patients whose melanoma lesions were injected with immunotherapy DNA material and then subjected to the short pulses that allowed the material to enter the tumor cells. Electric pulses were applied using proprietary applicators and electroporation equipment supplied by Inovio Biomedical Corp. in San Diego. The study found that electroporation was a safe and effective way to deliver the DNA material, without the risks and inefficiencies of other methods.
IL-12 plasmid was the DNA material that was used. It is a cytokine that stimulates both adaptive and innate immunity, helping the body to fight cancer. Biopsies of the lesions that were treated showed that more than half had at least 50 percent tumor necrosis, and that 32 percent had complete tumor necrosis.
"Twenty-four patients were treated at seven dose levels, with minimal systemic toxity," according to the paper. "Transient pain after electroporation was the major adverse effect. Post-treatment biopsies showed plasmid dose proportional increases in IL-12 protein levels as well as marked tumor necrosis and lymphocytic infiltrate. Two of 19 patients with nonelectroporated distant lesions and no other systemic therapy showed complete regression of all metastases, whereas eight additional patients showed disease stabilization or partial response."
"We are encouraged by these results. With this approach we were able to treat a small number of lesions and not only see regression in treated lesions but we also observed regression of non-treated lesions. Currently, Dr. Adil Daud and I are working on an additional study to continue this work and to confirm these results," Heller said.
The researchers, who were led by Daud, now at the University of California at San Francisco College of Medicine, assert in their conclusion, "This first human trial to our knowledge of gene transfer utilizing in vivo DNA electroporation in metastatic melanoma showed that it is safe, effective, reproducible and titratable. Electroporation of IL-12 plasmid into metastatic melanoma seems to have some activity in metastatic melanoma, and further evaluation is warranted." The researchers noted that earlier studies had suggested that augmented innate and adaptive immunity and tumor necrosis at the site of treatment could result in regression of distant tumors.
While at USF, the Hellers received more than $10 million in research funding, mostly from the National Institutes of Health (NIH). At the Reidy Center, they have joined Karl Schoenbach, the Batten Endowed Chair in Bioelectric Engineering who is recognized as a pioneer in the field of bioelectrics and who founded the center five years ago. In 2006, Schoenbach and other Reidy Center researchers reported their study showing that millionth-of-a-second pulses of electricity alone will destroy tumor cells and bring complete remission of melanomas on the skin of mice. The researchers also have reported the development of strategies using antennas to zap tumors inside the body.
The formal mission of the Reidy Center is to increase scientific knowledge and understanding of how electromagnetic fields interact with biological cells, and to apply this knowledge to the development of medical diagnostics and therapeutics, as well as environmental decontamination. The mission has been supported by numerous grants, including one for $5 million from the Air Force Office of Scientific Research.
Earlier this year, a Reidy Center team led by associate professor Andrei Pakhomov received a $1.1 million grant from NIH for a study titled "Cell Death Induction by High-Voltage, Nanosecond-Duration Electric Pulses (nsEP)." Pakhomov's collaborators are Schoenbach and Juergen Kolb, assistant professor of electrical and computer engineering.
With the grant, Pakhomov is exploring the biological reasons behind the center's remarkable success zapping tumors on mice. Researchers at the center have a good understanding of the net result of directing ultrashort pulses against cells. Now they want to know why the pulses are so effective. Before experimental treatments can evolve into therapeutic applications on humans, this fundamental research on cell function is required.
The Reidy Center and Schoenbach, via ODU, led a recent research initiative that brought together bioelectrics and related researchers from the Harvard/MIT Health Science Center, University of Texas Health Sciences Center, Washington University, the University of Wisconsin and Eastern Virginia Medical School. In addition, the center has leveraged the increasing interest in bioelectrics outside the United States. An international research consortium for bioelectrics formed in 2005 had ODU, Kumamato University in Japan and Universitat Karlsruhe in Germany as founding members. In 2006, the University of Missouri and the Institute for Low Temperature Plasma Physics in Greifswald, Germany, joined the consortium.