By Debbie Strickland

Special To BioWorld Today

Washington - A gene-therapy approach to treating cancer using interleukin-12 is now in Phase II human trials, a University of Pittsburgh researcher reported at the American Society of Gene Therapy's 2nd Annual Meeting.

Michael Lotze said the Phase II trial initially will seek to enroll 14 melanoma patients and 14 with head and neck cancer. Lotze is the university's chief of the division of surgical oncology and co-director of its human gene therapy program.

So far, six melanoma and three head-and-neck cancer patients have been enrolled in the study. The treatment uses a technique that consists of insertion of the two genes that together code for IL-12 into cultured autologous fibroblasts, cells that were selected because of their fast rate of replication. After four to six weeks, the cells are injected into tumor sites, where production of the IL-12 protein enhances immune response to cancer cells.

Serving as the bridge between the natural or innate immune response and the adoptive immune response mediated by T cells and natural killer cells, IL-12 is produced by dendritic cells and other immune cells that normally are the first to encounter and react to foreign, disease-causing substances. In an 18-patient Phase I/II trial in advanced cancer, the IL-12 therapy reduced tumors in 28 percent of patients.

Compared to direct injection of a recombinantly produced protein product, the gene therapy approach offers the potential advantage of less toxicity and a longer half-life, Lotze said, noting that the protein conceivably could be engineered to overcome those barriers, but for now a gene therapy approach looks promising.

If a 20 percent response rate is achieved, he said, the Phase II trial will be expanded, and at some point, the testing may undergo a bigger change - the researchers may switch to autologous cultured dendritic cells as the gene carrier.

"We are now modifying our IND to use dendritic cells," Lotze said. "They appear to be able to lead the charge in initiating immune response and maintaining immune response."

Another advantage is their speed of replication, which tops that of fibroblasts by a wide margin.

"With dendritic cells [the culturing and preparation] takes a week, as opposed to a month or six weeks with fibroblasts," he said. The shorter time line could prove crucial in treating patients with rapidly growing cancers.

Dendritic cells also appear able to traverse the blood-brain barrier - they have done so in murine models - and thus may be able to chase metastatic cells into their brain hideaways.

Savio Woo, the society's president-elect, reported on another approach, currently preclinical but heading for human trials this year, that seeks to harness the power of IL-12. In the murine colon cancer study, an adenovirus-delivered IL-12 gene therapy was combined with a monoclonal antibody agonist to murine 4-1BB, an activation molecule expressed on primed CD4+ and CD8+ T cells.

The therapy stimulated anti-tumor immunity and, more importantly, resulted in 80 percent to 100 percent survival, even when doses of the gene therapy were cut 18-fold.

Woo is director of the Mount Sinai Medical Center's Institute for Gene Therapy and Molecular Medicine in New York.

The ASGT's meeting this year has doubled in size, with more than 2,000 attendees and 1,000 talks on prospective gene therapies for everything from hair loss to obesity. The meeting runs through Sunday. Additional information is available at