Penn researchers score an early gene therapy success on leukemia

With his blood cancer progressing and standard chemotherapies no longer working, the patient decided to try an experimental gene therapy at the University of Pennsylvania.

Twenty-two days after getting a very low dose, he had to be hospitalized because of toxic effects on his kidneys and liver - a problem the researchers had anticipated but considered unlikely.

And then, the very next day, something happened that the researchers had not anticipated, despite 20 years of refining the gene therapy.

Tests showed the 64-year-old patient's chronic lymphocytic leukemia was gone. Eradicated.

The disease also disappeared in another patient, and dramatically regressed in a third. All three remain in remission, the longest enduring almost a year.

"It exceeded our wildest expectations," said Carl June, a gene therapy pioneer who led the work.

On Wednesday, two prestigious journals - New England Journal of Medicine and Science Translational Medicine - simultaneously published the Penn breakthrough. June's team genetically engineered each patient's T cells - the big guns of the immune system - to recognize and attack the leukemia cells, then stand guard against the disease.

In an editorial in New England Journal, two oncologists called the results "impressive." But they also cautioned that toxic effects, known and as yet unknown, "could pose substantial problems."

Only wider testing, wrote lead author Walter J. Urba of the Chiles Research Institute in Oregon, will show whether the breakthrough is "an authentic advance" toward a novel medicine, or yet another "lead that runs into a barrier."

For the 64-year-old patient, the answer is already clear. He declined to be identified by name, but  wrote an essay about his experience for Penn's website.

"I'm healthy and still in remission," he said. "I know this may not be a permanent condition, but I decided months ago to declare victory." (Another patient also declined to be named. The third is William Ludwig, 65, a Philadelphia area resident.)

Gene therapy has emerged from the pall of the 1999 death of Arizona teenager Jesse Gelsinger in a Penn trial that revealed ethical and regulatory problems. It has even had successes, notably in treating a rare form of blindness and an inherited immune deficiency disease.

Still, the field remains highly experimental after more than two decades.

Gene therapy harnesses the insidious ability of viruses to slip DNA into the cells they infect. By using these invaders to insert DNA that is helpful rather than harmful, gene therapy can theoretically treat everything from heart disease to infections to cancer.

June's team, which includes Bruce Levine, David Porter and Michael Kalos, has made steady progress in using gene therapy against HIV and blood cancers - but nothing as big as their latest achievement.

"We don't actually know the magic ingredient yet," June candidly admitted.

To make an effective therapy, the researchers had to overcome a fundamental obstacle: cancer arises in the body's own cells, so the immune system is very tolerant of these renegades.

The researchers' strategy involved taking the patient's T cells and using a deactivated virus to insert a specially-designed gene. This gene enabled the T cells to recognize and attack B cells, the blood component that turns malignant in chronic lymphocytic leukemia as well as some other blood cancers.

But that wasn't the breakthrough.

In previous studies at numerous centers, designer T cells worked only briefly and weakly before being wiped out by the body's still-mysterious defense systems.

In the new study, in contrast, the T cells multiplied a thousand-fold in the patient's body, wiped out B cells, and then matured into "memory" T cells - permanently programmed to go after their target. The patients' ongoing remissions suggested the T cells had developed memory, but the researchers also showed it by re-collecting some of the T cells and using them to kill B cells in lab dishes.

Kalos called the T cells' persistence "unprecedented."

Then again, wholesale destruction of B cells can be perilous. One patients required care for "tumor lysis syndrome" a potentially life-threatening complication. Basically, his circulatory system became so clogged with dead B cells - almost two pounds' worth, the scientists estimated - that his kidneys and liver couldn't get rid of it fast enough.

"It was serious," Levine said. "But it was something we had anticipated as a possible side effect and we were prepared for it."