Penn research offers new hope for rare cancer

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 treatment.

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

The deadly disease also disappeared in another advanced-stage patient, and dramatically regressed in a third. All three remain in remission, the longest lasting almost a year.

"It exceeded our wildest expectations," said Carl June, a gene therapy pioneer at Penn's Abramson Cancer Center 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 malignant cells, then stand guard against the disease.

Although chronic lymphocytic leukemia is rare and slow-growing, the study has implications for a large group of blood cancers, including many lymphomas, that are diagnosed in 87,000 Americans a year. In these cancers, malignancy arises in B cells, which are the target of the Penn gene therapy.

In an editorial in the New England Journal, two oncologists called the results of the new study impressive. But they warned that toxic effects, known and unknown, "could pose substantial problems."

Only wider testing will show if the breakthrough is "an authentic advance" toward a novel medicine for B-cell malignancies, or yet another "lead that runs into a barrier," wrote lead editorialist Walter Urba of the Chiles Research Institute in Oregon.

For the 64-year-old patient, the answer is already clear. Although he did not want to be identified by name, he 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." (A second patient also declined to be named. The third patient, William Ludwig, 65, declined an interview.)

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. There have been successes, notably in treating a rare form of blindness and an inherited immune deficiency disease.

Still, the field remains experimental after 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 anything from heart disease to infections and 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 the latest achievement. "We don't actually know the magic ingredient yet," June acknowledged.

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 malignant blood component.

But that wasn't the breakthrough. In previous studies, designer T cells worked only briefly and weakly before being wiped out by the body's still-mysterious defenses.

In the new study, in contrast, the T cells multiplied a thousandfold 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 confirmed it by recollecting some 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. The patient, 64, required care for "tumor lysis syndrome," a life-threatening complication. Basically, his circulatory systems became so clogged with dead B cells - two pounds' worth, the scientists believe - that his kidney and liver couldn't get rid of the debris 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."

Another complication arises because the designer T cells kill both healthy and cancerous B cells, so the patients' supply can be permanently depleted.

B cells, which help fight viral and bacterial infections, are not indispensable to the body. Indeed, the chemotherapy drug Rituxan, used to treat many types of blood cancers, targets B cells. However, patients who lack B cells need regular intravenous doses of immunoglobulins to reduce their chances of infection.

The editorial's authors note that overactive T cells can be curbed by immune-suppressing drugs. Researchers are also working on equipping designer T cells with a suicide signal "to kill the cells when they are creating mischief."

But if fatal side effects develop soon after gene therapy is given, even a suicide fail-safe wouldn't have time to work, say the editorialists. Last year, researchers at Memorial Sloan-Kettering Cancer Center in New York reported such an abrupt and unexpected death in a trial of a T-cell gene therapy for chronic lymphocytic leukemia.

While many questions remain unanswered - and June is quick to tick them off - he and his collaborators see new hope for patients with B-cell malignancies.

Now the only potentially curative therapy for such cancers is a stem-cell transplant (sometimes called a bone-marrow transplant), but many patients don't qualify for the risky procedure and many who do are not cured.

In his essay, the patient alluded to this new hope: "When I was a young scientist, like many I'm sure, I dreamed that I might make a discovery that would make a difference to mankind. I never imagined I would be part of the experiment."

View video of Penn researchers describing the breakthrough - and read a patient's perspective - at www.philly.com/healthEndText