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http://www.phillynews.com/inquirer/97/Oct/03/front_page/GENE03.htm
©1997 Philadelphia Newspapers Inc.

Gene therapy has proven to be safe. Still unknown, though, is its effectiveness.

One in a series of occasional articles on gene therapy research.
By Donald C. Drake
INQUIRER STAFF WRITER

Joan and Donald Hardy didn't talk about the cancer in Donald's chest as they drove to the University of Pennsylvania Medical Center on Sept. 19 for his monthly checkup.  They always avoided the subject when he went to the doctors. The fear that the cancer had started growing again was too frightening.

Donald Hardy had been making this trip for almost two years, ever since he volunteered for a gene therapy experiment and let Penn doctors infect him with genetically altered viruses designed to fight his cancer.

Hardy had mesothelioma, a rapidly fatal form of cancer that attacked the chest wall and lining of the lungs. Hardy was the first mesothelioma patient in the world to be treated with this type of therapy.

Mesothelioma has defied all forms of conventional therapy. Practically all patients are dead or in advanced stages of the disease two years after diagnosis. But in Hardy, the cancer had become mysteriously quiescent.

Still, whenever the couple made this trip to Penn, in the back of their minds was the fear that this time the doctors would find something with their physical exams and X-rays and CAT scans, that this time they would announce that the cancer had started growing again.

It's now four years since James M. Wilson came to Penn from the University of Michigan with the mandate to set up a world-class gene therapy program and, it was hoped, to start curing diseases with a radically new type of treatment.

A lot has happened since he arrived in West Philadelphia during a record-breaking March blizzard in 1993.

He's set up the Institute for Human Gene Therapy, which has grown to 170 scientists and support staff, is financed with $20 million a year in government and foundation grants and is housed in laboratories occupying five buildings on the Penn campus, not counting two full floors that will be in a biomedical research building now under construction.

In that time, Penn scientists have started human trials with gene drugs for cystic fibrosis, the inherited liver disease OTC (ornithine transcarbamylase), mesothelioma and brain cancer. Trials of drugs against melanoma and colon, ovarian and breast cancer are being planned.  The four drugs already in use, which have been given to 54 patients, have turned out to be extremely safe. Other than minor reactions such as mild fevers and skin rashes that quickly went away, the drugs have had no side-effects.

But so far there's no evidence that any of the drugs have been effective against any of the diseases.  Even so, Donald and Joan Hardy are convinced that the gene therapy has stopped Donald's cancer, at least for the moment.

Daniel Sterman, one of the doctors taking care of Hardy, was always a little nervous when he came in for checkups.

Unlike the basic gene therapy researchers, sequestered in labs far from dying patients, the 33-year-old Sterman was a hands-on physician whose focus was on keeping his desperately ill patients alive, not just solving scientific puzzles.

Hardy was the first patient to be treated in the study, which now involved 23 patients. Since Hardy underwent therapy in November 1995, nine of the other test subjects had died and the disease was steadily progressing in seven of the others, despite treatment. The remaining seven showed no progression of disease.  With so many patients dying or doing poorly, Sterman was relieved to see someone doing well, but how long would this last?

Hardy, who had gotten mesothelioma during his 34-year career working with asbestos, had become something of a hero or ``poster boy'' in asbestos-worker circles.  In August, he and Sterman flew to Las Vegas to address the annual meeting of the International Association of Heat and Frost Insulators and Asbestos Workers.

Both received standing ovations from the more than 800 attending the meeting when the very hardy-looking Hardy was presented as a mesothelioma victim who had volunteered to test an exciting new treatment for the lethal disease and was doing well.

In his speech, Hardy urged his former colleagues not to shy away from cancer tests, a common practice because the disease was so relentless, but to get frequent checkups because gene treatments were now available. The implication was that gene therapy had helped Hardy and it might help them, too.

Sterman followed Hardy to the podium and described the Penn program. He was very careful, however, not to suggest that gene therapy had saved or even benefited Hardy.

Sterman had reason to be cautious.

Not only was there no evidence that any of the experimental drugs at Penn was working, there is no proof that any form of gene therapy is effective.

It's not for want of trying. The mesothelioma trial was one of more than 200 human gene therapy trials started in this country since the first human was given a gene drug in 1990. And gene drugs have been tried against dozens of diseases involving hundreds of patients.

After an initial wave of enthusiasm and heartening news reports in the early 1990s, the field has largely fallen from public view.   At first it had looked so promising and, in a way, easy to do. All doctors had to do was insert disease-fighting genes into the cells of patients. The genes would turn the cells into tiny biochemical factories.

And there was no problem getting the genes to the cells. They could be inserted into viruses, which would deliver them to every cell they infected. Depending on the type of gene used, the cells would churn out proteins to combat heart disease, cancer, AIDS, arthritis, genetic diseases or cancer like mesothelioma.

Animal studies looked very encouraging. But once human trials started, scientists quickly discovered that nature wasn't going to be so obliging to follow the script they had written to usher in a new era in medicine.

Though the viruses did deliver the genes to some cells, not enough cells were being infected to produce sufficient biochemicals to combat disease.

The scientists' hopes were being dashed by an ironic turn of events. Unable to distinguish the therapeutic viruses from viruses that cause disease, the patients' immune systems were destroying the gene-carrying vectors and the cells they infected.

Hardy was waiting in one of the examining rooms in Penn's clinical research center when Sterman arrived to examine him.

Sterman could see the moment he walked into the room that Hardy was doing well, which was no surprise because the two had been together only a few weeks earlier in Las Vegas.

Sunburned from playing golf and cheerful as usual, Hardy took off his shirt and Sterman began his examination. If the cancer had grown, the mass would block the sound of Hardy's lungs filling and expelling air and cause a dull sound when Sterman percussed Hardy's back.

Thumping on Hardy's back, Sterman heard the drumlike sound of a healthy lung being percussed. A small area over the lower right lung reverberated with a dull sound, but it was no larger than it had been when Sterman examined him two years earlier. He pressed the end of his stethoscope against Hardy's back and heard clear breath sounds.

Relieved, he told Hardy that it looked good. But both men knew that this was a crude assessment. Only the radiologist could determine with any certainty if the cancer was growing.

After the exam, Hardy went down the hall for an X-ray and CAT scan. Then he and Joan returned home to wait for the call telling them what had been found. Usually they got word the next day, but it was Friday. They would have to wait until Monday.

That night Sterman did not go home but drove to Absecon, N.J., where the Institute for Human Gene Therapy was holding its annual retreat to review what the Penn scientists were doing and hear papers from leaders in the field.

Sterman was scheduled to report on the mesothelioma trial. Hardy was represented by a dot on a slide that Sterman carried in his briefcase.

Sterman presented the data without emotion to the 160 researchers and students gathered in a meeting room at the Seaview Resort -- 23 patients treated, nine dead from their disease, seven doing poorly and seven doing well.

Five of the patients showed no progression of disease even though they had been treated many months earlier and should have been getting sicker by now.

Hardy was one of those five. The disease is so deadly that 50 percent of patients are dead within two years of diagnosis and 97 percent or more are close to death.

Sterman was at a loss to explain why the five patients were doing well. Some received high doses of the drug and some low doses. Some patients showed no evidence that the vectors had successfully delivered the genes to the cells, and in other patients genes had clearly been successfully transferred.

The only common factor among the patients was that they had all been diagnosed in early stages of disease, but even so they should have shown disease progression by now. One possible explanation, Sterman said, was that the treatment caused an inflammatory reaction that stopped the cancer cells from growing, at least for the moment.

The gene therapy treatment had proved so safe, Sterman said, that plans were underway to do a phase II trial, in which the drug's effectiveness would be tested. Phase I trials, such as Hardy was in, test only safety.

The phase II trial would involve many more patients -- 100 -- and four or five medical centers.

The other Penn trials discussed at the meeting were all phase I, and those results, too, showed no serious side-effects, even though the doses of the drugs were being steadily increased.

Penn ophthalmologist Jean Bennett reported progress in testing different vectors in animals who had retinitis pigmentosa, a leading cause of blindness in humans.

She said gene treatment temporarily delayed the onset of blindness in dogs born with the disease. She said she was about to start trials with a new vector called AAV (adeno-associated virus), which might confer more lasting protection.

Katherine High of Children's Hospital reported success using AAV with a gene that may repair the genetic defect that causes the bleeding disease hemophilia. In mice, it had produced Factor IX, an element that promotes blood clotting, which hemophiliacs lack.

High is preparing to try the treatment on dogs with hemophilia. If it works, she will move to human trials, possibly within a year or so.

Inder M. Verma of the Salk Institute, a leading gene therapist, sounded a cautionary note at the meeting. Pointing out that more than 200 human trials had been conducted and still no proven therapy was in sight, he said scientists must learn much more about the basic science of cell biology and immunity before major problems blocking success could be solved.

While Sterman was attending the retreat in Absecon, Hardy was a few miles away on a golf course shooting in the high 80s and his wife was in their Toms River home.

It wasn't until Monday afternoon that Sterman got the written report from the radiology department. He immediately called Hardy.

The radiologists found no signs that the cancer was growing, Sterman said. The CAT scan was indistinguishable from early scans.

"Well. I guess that's good news,'' Hardy said.

"It certainly is,'' Sterman said.

** POSTED OCTOBER 8, 1997 **