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October 28, 2005

Biogen Idec Gene Drug Gives Man Second Chance at Survival

Knight Ridder Newspapers

PHILADELPHIA: Harvey Harris settled into the bed at the Hospital of the University of Pennsylvania, ready to endure yet another round of tests to check the aggressive cancer growing in his chest.

He wasn't feeling optimistic.

By most counts, Harris should have been dead by now. He had mesothelioma, caused by a lifetime spent working around asbestos.

Six months earlier, after conventional chemotherapy had failed him, Harris decided to try an experimental treatment. He was infused with hundreds of billions of viral particles genetically engineered to rev up his body to attack the cancer.

Then, in July, he ventured even further into unproven territory. He became the first patient in the clinical trial at Penn to get a second dose of the gene drug.

Soon he would have an answer. Had the gene therapy stopped the cancer? Or was the tumor, which enveloped his right lung like a rind, now advancing, steadily robbing his energy and breath?

Harris braced for the worst. The day before, he'd had a CAT scan near his Gibbsboro, N.J., home and then held up the film to a skylight in his family room. To his eye, the cancer looked worse.

Sick as he felt, Harris, a slight, balding man, was full of plans. He was only 61.

Jeanette, his wife, was throwing him a birthday party in a few days, and for the first time in more than a decade, he and his three grown children would all be together. He still needed to clean the porch and pick the music. There were ribs and chicken to cook.

For the first time in his life, he had plenty of money.

Cancer or no cancer, he and Jeanette were heading to their new home in Florida as soon as the temperature dropped. He was imagining a life of warm days, lots of fishing, and time for his pottery.

When he'd first signed on to the experimental gene therapy, Harris hadn't been banking on a cure. Squeeze out one more year _ that's what he wanted. One more good year, maybe two. Then he'd see what happened.

He was close to dozing off when the nurse for the gene-therapy trial appeared at his bedside.

She was holding Harris' CAT scan report, which had just been faxed.

Harris had not expected to know a thing until he met later in the week with Dr. Daniel Sterman, who led the clinical trial.

Now, out of the blue, his fate was right in front of him.

Of all the cancers, mesothelioma is among the most merciless. Current treatments are limited, and so Penn researchers are turning to one of the newest medical technologies to fight the disease.

The cancer, which attacks the linings of the chest and abdomen, can be hard to detect and often advances rapidly. Patients usually die within eight to 14 months of diagnosis.

The cancer is primarily caused by exposure to asbestos, fibrous mineral once common in heating insulation, vinyl flooring, roof shingles, and other industrial products.

Asbestos dust can penetrate the lungs and lodge in the chest lining, causing damage that does not become apparent for decades. Generations of shipyard workers and factory and construction workers have breathed in asbestos particles. The material was phased out starting in the 1970s, but it's still present in many buildings. An estimated 2,500 to 3,000 people will be diagnosed this year with mesothelioma in the United States.

Harvey Pass, a thoracic surgeon and mesothelioma expert at New York University, said an even bigger epidemic of disease is brewing in lesser-developed countries where asbestos-containing products continue to be used.

The disease has long been a focus for Sterman and his team, including thoracic surgeon Larry Kaiser and pulmonologist Steven Albelda. They began testing gene therapy on the disease 10 years ago with a different drug. The first of 34 patients from that trial is still alive, as are two others.

Back then, the field of gene therapy was hot. It seemed to offer hope for curing a list of ills — cancer, cystic fibrosis, hemophilia and more.

But in 1999, the field nearly imploded when a teenager died in a gene-therapy trial at Penn, then a national leader in the field. Federal investigators ordered a halt to the university's eight trials, including the one for mesothelioma, after the death of 18-year-old Jesse Gelsinger. They said patient safety could not be guaranteed.

Gene-therapy trials did not resume at Penn for more than three years. Currently, the university has three trials, including the one for mesothelioma.

There are now 45 gene-therapy trials registered with the National Institutes of Health, down from a peak of 91 in 1999.

"Ten years ago, there was a lot of hype, and things probably were overpromised. It's kind of where stem cells are today," said Mark Kay, a Stanford University researcher and president of the American Society of Gene Therapy.

"I think people in the field feel there's a sense of progress, but it's taken longer than people expected."

One February morning in 2004, Harris was dressing for work when he became so short of breath he could barely walk.

He made it downstairs to the sofa and collapsed.

For months he had been feeling winded and tired, but checkups found nothing.

On that day, the pressure in his chest was unbearable. His doctor sent him to Kennedy Memorial Hospitals-University Medical Center/Stratford.

X-rays revealed that Harris' right lung was partially collapsed, compressed by a sea of fluid in his chest. Doctors suctioned off three liters and cut through his rib cage to get tissue samples.

The diagnosis of mesothelioma baffled him.

"What the hell is that?" he asked.

As it was, Harris had a classic history for the cancer. In the Navy, he had chipped asbestos off pipes. Then, he'd worked for nearly 13 years at the Owens-Corning Fiberglas plant in Barrington, N.J., where he routinely handled asbestos.

"You inhaled the dust constantly," Harris testified for a lawsuit he brought against asbestos manufacturers.

His longest stretch of employment, about 17 years at the Naval Air Station in Pensacola, Fla., also involved asbestos.

Harris' doctor told him that removing the tumor wasn't an option. He began chemotherapy, which made him vomit. His pain was so bad he couldn't sleep. So he cruised the Internet, looking up mesothelioma.

From what he read, he felt he'd be in the ground in six months.

Then he discovered that at a medical center just across the river, something new was being tried.

Ten days before Christmas, he went to see Sterman.

Harris felt an instant connection with the young doctor. He liked the way Sterman listened to his story, not cutting him off as other doctors had. He also sensed Sterman's passion as he talked about his team's research.

Sterman is one of a growing number of researchers pursuing an approach called "immunotherapy," which tries to activate a patient's immune system to fight disease.

Penn is testing a gene drug, made by Biogen Idec, on mesothelioma and other chest tumors. The company said it is also testing the drug on colorectal cancer that has spread to the liver.

The drug ran into difficulty at another medical center in 2003, when a trial involving brain tumors was stopped after a patient experienced a serious complication, a Biogen Idec spokesman said. The firm declined to say more.

Penn's study was temporarily put on hold. The incident involved where the drug was injected, not its safety profile, said Joseph Sherwin, Penn's director of regulatory affairs. Penn was cleared to resume in about six weeks, he said.

The drug consists of a cold virus genetically altered to carry the gene for interferon beta, a natural human protein that helps fight disease. The treatment involves infusing 900 billion viral particles into a small space at the bottom of the chest cavity. If all went as planned, the gene-carrying viruses would be taken up by the tumor cells, and production of interferon beta would begin. The interferon beta, in turn, would marshal immune cells into action.

Harris appreciated the doctor's candor in saying his chances for a recovery were remote. The gene drug was being tested in a "Phase I" clinical trial, designed to study safety, not effectiveness. Many promising drugs at that stage never make it much further.

On March 7 of this year, after his cancer doctor said more chemo was pointless, Harris became the 10th patient to get the gene drug at Penn.

Harris knew there were risks in taking an unproved drug. But he had to try something; he couldn't just sit back and die.

He had his family and a new wife.

Over the next few months, he stood to become a well-off man, from settling his lawsuit with 13 companies that made asbestos-containing products.

He planned to build two houses in Jacksonville, Fla. — one to rent — and he had a myriad of interests. A high school dropout, he had collected enough college credits to jokingly declare himself a senior in five disciplines.

He really wanted to get back to his pottery and sculpture. He used to sell his artwork and had virtually abandoned the craft when he got sick.

Harris loved to work a chunk of clay, leaning forward to put his whole body into it.

"I let the clay dictate to me what it wants to do," was how he described his method. "Then at a certain point I have to take back over."

Maybe he could do the same with his cancer.

In late May, Sterman sat before a bank of computers, studying the before and after images of Harris' lungs.

Now that Harris had received one dose of the drug, Sterman wondered, could he get a second?

Sterman _ whose research team has received nearly $10 million from the National Cancer Institute _ had never given a repeat dose to anyone in the experiment, though he had certainly thought about it.

In mouse studies, the difference between one dose and two was dramatic. With one dose, up to 30 percent of mice with large mesothelioma tumors had been cured; with two doses, close to 70 percent had.

Sterman knew that what worked in mice often didn't work in people. But the mouse results offered a rationale for allowing a second dose.

When Harris asked if he could get one, Sterman amended the experiment to allow any patient in the trial to get it, but only if strict criteria could be met.

For Harris to qualify, his cancer would have to be considered "stable."

Sterman and his nurse coordinator, Adri Recio, took careful measurements on the screen of Harris' tumor from pre-therapy and post-therapy CT scans.

They found only a slight progression; his disease was stable.

Now Sterman would have to get the second dose approved by the hospital's institutional review board and the U.S. Food and Drug Administration.

Sterman went off to see Harris, who was waiting with his wife in an exam room down the hall. Harvey and Jeanette, a former social worker, had been married not even two years when he got sick.

"The measurements we took are almost identical, which by our criteria means you have stable disease," Sterman explained. He could get a second dose.

Harris, sitting on the exam table, clapped at the news, but Sterman added a caveat.

"You'll be another level of experiment," he warned. "It's always possible that they'll come back to us and say no."

Sterman drew a diagram to show what might be happening.

"We haven't stopped the tumor from growing, but we may have slowed its rate of growth."

Harris let out a relieved "thank you," but then, almost as an afterthought, asked what stage his cancer was in.

He was still stage 3, answered Sterman, on a 1 to 4 scale.

"I didn't realize I was so advanced," Harris said, looking dejected.

But just as quickly he was back to the positive _ another precious dose might soon be his.

"I'm going to go home and kick up my heels," he said.

On July 18, inside Penn's special unit for clinical trials, Sterman examined Harris one last time before administering the coveted second dose.

"Do you feel like a pioneer?" Sterman asked, checking Harris over.

"I feel like a pilot, ready to take off," Harris said.

Sterman picked up a thick syringe of solution containing 900 billion viral particles. Slowly, he injected it into a catheter leading to Harris' chest cavity. It took about two minutes.

Afterward, Sterman sat on Harris' bed and watched the monitors tracking his patient's blood pressure, heart rate and breathing.

The next hour would be critical.

Sterman believed in the treatment, but still, he was on guard. Every time you took an experimental therapy to a new level, there was risk.

The death of Jesse Gelsinger was not far from his mind.

It would be 60 days until follow-up PET and CAT scans would show whether Harris' cancer had responded. But there were more immediate concerns.

It was possible he could have an acute immune reaction right after the injection.

At first, the time passed uneventfully, and Harris was soon enjoying a ham sandwich for lunch.

By late afternoon, the chills and fever hit.

Harris began to shiver and called for a nurse to bring blankets. His temperature rose above 103. He ached. The nurse summoned Sterman.

The doctor reassured Harris that flulike symptoms were to be expected after the gene infusion. It meant that the viral particles were active.

All through the night, the fever and chills continued.

He tried to sleep but was too scared. Crazy as it sounded, he was afraid that Sterman would come back and suck the gene drug out of him. And that would mean losing his second chance.

Sometime before dawn, Harris fell asleep. When he woke, it felt like a new day.

He wondered what there was to eat.

Harris was running late. It was Sept. 15, the day he would learn if his second dose had done any good.

He had forgotten to set his alarm.

Two days earlier, the nurse had given him a preview of what the doctor's verdict might be. The way Harris figured it, no matter what his prognosis was, 19 months had passed since he was diagnosed with mesothelioma, and he was still alive. Even if he didn't benefit from the gene therapy, his participation could help people down the line.

"Uh-oh, got bad news," Harris said, taking a read of Sterman's face as he sat down in the exam room.

"No, I don't. No, I don't. In fact, I've got good news," Sterman said.

The doctor explained that the CAT scan showed no signs that the cancer had progressed. Even better, the PET scan, which measures the level of cancer activity, showed some improvement since the second dose. At the base of his lung, some cancer might have cleared.

"Hot dog!" Harris yelped.

The second dose could already have made a difference, Sterman said, and the immune response triggered by the drug might continue.

The cancer wasn't gone, but it wasn't any worse.

"It's a good birthday present for you," Sterman said.

"Thank you," said Harris.

Sterman and his team have much work left to do. Their study is way too small and too preliminary to draw broad conclusions.

They have not published findings but have talked about their experience at medical meetings.

Of the 10 patients treated with the gene drug since August 2003, seven are still alive. Three died from their advanced cancers, Sterman said, with no evidence that the gene drug shortened their survival.

Side effects included fever, headaches, and a temporary rise in liver enzymes, an indicator of potential toxicity, Penn's Sherwin said. He said none were unexpected.

The team is encouraged enough by the drug's performance to plan another Phase I trial, using two doses of the gene drug. Sterman and his colleagues also want to test the treatment in combination with chemotherapy and surgery.

As for Harris, there's no way to predict how long he has to live. Sterman will follow him closely in the coming months. Harris is already interested in other experimental treatments.

Two days after getting his results at Penn, Harris celebrated his 62d birthday. He set up a big party tent in the backyard and was finishing a batch of potato salad as his guests arrived.

His children and three grandchildren came, all six of his living siblings, friends from the old neighborhood, and a Navy buddy from way back.

"It's nice," Harris told his friends, "to squeeze in a birthday before winter settles in."