WSJ front page story: Gene Therapy, Much-Maligned Recently,
Shows Promise in Some Cancer Trials
By LAURA JOHANNES
Staff Reporter of THE WALL STREET JOURNAL
In the summer of 1997, Patricia Aneff's lung tumor seemed invincible. It had nasty tentacles that made surgery out of the question. Three rounds of chemotherapy "made me look like E.T. but didn't do zippo to the tumor," says the Abilene, Texas, woman. "I didn't think I would live to see the millennium."
Then Ms. Aneff became a test subject in an entirely new way to attack cancer: gene therapy. A lab test found her tumor cells had defective genes known as p53, whose function is to brake runaway cell growth. When doctors injected her tumor with sound copies of p53, it shrank into a little ball, and surgeons handily removed it. Mrs. Aneff celebrated New Year's Eve with friends and then headed to a midnight church service. She now appears to be cancer-free.
Gene therapy seeks to treat diseases by using biological sleight-of-hand to insert replacement genes into cells that have missing or defective copies of those genes. It has come under heavy scrutiny since the November death of 18-year-old Jesse Gelsinger, who had a genetic liver disease, in a trial at the University of Pennsylvania.
Critics note that gene therapy has now been tried for a decade with few positive results. In trial after trial, scientists have injected genes to treat diseases such as cystic fibrosis, only to find nothing happened, probably because the genes never got into cells where they were needed.
Small Successes
But just as public opinion on gene therapy has soured, several significant successes have been achieved. In preliminary trials at Children's Hospital in Philadelphia, children with hemophilia were treated with genes that helped their bodies make a blood-clotting protein they lacked. Boston researchers have relieved chest pain caused by clogged arteries by injecting hearts with genes that caused new blood vessels to grow. And French doctors recently reported initial successes in treating children with a rare genetic defect that destroys their immune systems and forces them to live in isolation.
Only in cancer, however, has gene-replacement therapy progressed into Phase III trials, the final-stage research aimed at getting Food and Drug Administration approval. Pharmaceutical companies Schering-Plough Corp. and Aventis SA, which is working with closely held Introgen Therapeutics Inc., were so impressed with early results that they recently launched large studies in ovarian and head-and-neck cancers.
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Gene Therapy Trials
Clinical trials for cancer using the p53 gene include the following:
HEAD AND NECK CANCER
Introgen Therapeutics Inc./Aventis SA. Phase III just beginning.
LUNG CANCER
Introgen/Aventis. Phase II trial of p53 in combination with radiation.
OVARIAN CANCER
Schering-Plough Corp. Phase III just beginning.
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It is by no means certain the trials will succeed. Scientists fear that gene therapy may kill only those cancer cells in the small area around the injection, not the entire tumor. And even if it annihilates the entire tumor, the therapy is powerless against any malignant cells that may have migrated elsewhere in the body. Even with the best results from these two tests, it will be at least three years before the FDA approves gene therapy for cancer outside of clinical trials.
Ray of Hope
But these two final-stage trials represent a ray of hope. And Introgen has also seen initial promising results in a Phase II, or midstage, lung-cancer trial that is a follow-on to earlier trials involving Ms. Aneff and others. In addition, doctors are testing p53 gene therapy for possible effect against prostate, breast and brain cancers.
"I don't think anybody harbors the illusion that you can take one gene off the shelf, inject it, and bingo, all tumors disappear," says James Zwiebel, an oncologist at the National Cancer Institute, which finances several gene-therapy trials. Still, he says that eventually, "it is very likely that p53 replacement therapy will become part of our standard treatment for some cancers."
Over the past several years, about 600 people have been infused with the p53 gene. The gene is known broadly as a "tumor suppressor," one of whose jobs is to sense when there is a problem with a cell and direct it to commit suicide. So it's a problem if the gene isn't doing its job.
The powerful role of p53 in human cancers was demonstrated by researchers at Johns Hopkins University 11 years ago. The gene -- which can be damaged by excessive sunlight, carcinogens such as cigarette smoke, or random duplicating errors during cell division -- is believed to be defective in 50% to 75% of human cancers, says Johns Hopkins professor Bert Vogelstein, whose lab did the pioneering work.
Useful Virus
To insert an intact copy of the gene into cells that lack one, scientists use a virus. Its harmful core is removed, and the p53 gene is inserted into the virus. The theory: The virus will do what viruses normally do -- infect cells. But instead of bearing a pathogen, they will carry in a beneficial gene.
In cancer, experimental gene therapy has caused some severe side effects such as high fevers, but it has proved less toxic than chemotherapy.
To date, 230 patients with head-and-neck cancer have been treated in three Phase II trials, says Antoine Yver, senior director of oncology gene research at Aventis, a drug company formed last year by the merger of Hoechst and Rhone Poulenc. Some tumors shrank dramatically. Others stopped growing -- not forever, perhaps, but long enough to buy the patient a few more months.
Of the patients, 6% saw their head or neck tumors shrink by half or more. While that was less than Aventis had hoped, by another measure the therapy was working better than expected: Overall, 26% of patients found their tumors either shrank or stopped growing. Looked at another way, given that some patients had more than one cancerous growth, 60% of the tumors injected either shrank or stopped growing for between two and 18 months.
This may not sound like much. But in the test group -- patients expected to live only about four months -- even a few extra months of life could be enough to win FDA approval, and possibly make this the first gene therapy on the market.
One doctor who took an early interest in the gene was Jack Roth, a lung-cancer surgeon who was frustrated by his enemy's power. "I was operating on a lot of patients, but it was clear it wasn't working," Dr. Roth says. "We needed to do something else."
Intrigued by the Johns Hopkins reports on p53, Dr. Roth began experiments in which the gene was shot into lung cells of special mice with human tumors. "The tumors didn't grow at all, or regressed," Dr. Roth says. After dozens of animal studies, he founded Introgen in 1992 to raise money for human trials. The Austin, Texas, company has filed to make an initial public offering; Dr. Roth owns 7% of it and stands to benefit if its IPO is a success.
In the first patient, a 60-year-old man with a lung tumor unresponsive to radiation, the cancer disappeared. "It was very exciting. It was the first clue something was going on," Dr. Roth says.
Then, in a reminder of the limitations of the therapy, the patient died four months later from another tumor, in his kidney.
Cold Virus
Although the patient's extra months represented an advance, the kind of virus used was difficult and costly to manufacture. Seeking another way to deliver the gene to cancer cells, Introgen turned to an adenovirus, a virus of the sort that causes colds. It was emptied of its normal contents, and p53 was inserted.
In association with Dr. Roth, Gary L. Clayman, a surgeon at M.D. Anderson Cancer Center in Houston, began using the adenovirus for experimental gene therapy on 33 people with head-and-neck cancer in 1995. Although steps had been taken to render the virus harmless, "we didn't really know" whether it could still cause harm, Dr. Clayman says. He wore a double set of gloves, washed carefully -- and worried about bringing home a virus to his newborn son.
The first few doses caused no ills, but no tumors shrank, either. Then researchers increased the dose a hundredfold, and began to see shrinkage. Introgen expanded the trials and began working with Aventis, which is financing the work in exchange for possible future marketing rights.
The patients in the expanded trials, all with advanced cancer unresponsive to other therapies, were expected to live only a few months. Gene therapy clearly had an effect, halting the growth of some tumors and shrinking some others. "The surprising thing for us investigators was that it worked at all," says John T. Hamm, an oncologist in Louisville, Ky. "Some people are disappointed that gene therapy hasn't revolutionized the world yet. It's a question of glass half empty or half full."
Leonard Taylor, a 50-year-old lawyer, was one of the lucky ones. He had a golf-ball-size tumor on his neck, which hurt his ability to chew and caused him to lose 40 pounds. It was too close to an artery for surgery. Chemotherapy shrank it at first but stopped working after six months.
Mr. Taylor then saw a newspaper ad for gene-therapy trials and signed up. He got his first shot in June 1998. Within three months, he was elated to find that the tumor had started to shrink. Now, nearly two years later, it appears to have disappeared except for a mass of scar tissue.
Doctors don't know if any live cancer cells are still present, so he goes back every month for another gene-therapy shot. "We're out there where no one has gone before," Mr. Taylor says. "We'll just take it one shot at a time and see how it goes."
The Safety Issue
Though the Jesse Gelsinger death raised alarms about safety, gene therapy for cancer is less toxic than chemotherapy. Two patients in Introgen's initial trial died for unknown reasons, leaving open the possibility that the therapy was responsible. But in a safety analysis prepared for federal authorities, Aventis found that, of 307 patients treated in Phase II trials for all types of cancer, there were no deaths, and only 3% had serious side effects, the most common being fever, infection or bleeding in the tumor. With chemotherapy, five times that many would have had serious side effects, Aventis's Dr. Yver says, and about 3% would have died. One reason for the relative safety of gene therapy for cancer may be that genes are injected into the tumor or right next to it, avoiding other parts of the body.
Shown this data, federal officials have largely let cancer trials continue, while halting several gene-therapy trials for other conditions. The government did stop an early-stage cancer trial at Schering-Plough, involving colorectal and liver tumors, pending a safety analysis. But Schering's final-stage ovarian-cancer trial will proceed.
Now comes the real test: large Phase III trials comparing gene therapy to standard treatments. In a trial Aventis and Introgen have just begun, about 240 people with head-and-neck cancer will be randomly assigned to get either the gene therapy or a mild chemotherapy drug. The test subjects will have cancer that has recurred, and they will be too frail for powerful chemotherapy or have cancer that hasn't responded to it. They'll have a median expected survival of four months; the goal is to see if the therapy can make them live about seven months.
"It works. Tumors shrink," Dr. Roth says. "The question is, does it work as well or better than existing treatments?"
There is ample reason for concern. In 1996, Novartis AG began the first Phase III trial of any kind of gene therapy, seeking to treat a deadly brain tumor called glioblastoma. The idea was to insert a gene that made the tumor vulnerable to a drug. Early trials had shown dramatic tumor shrinkage. But the big, final-stage one found that it didn't extend survival.
Aventis, hedging its bets, is also planning a separate trial to see whether gene therapy can make cancer cells more vulnerable to chemotherapy. A second 300-patient study will test p53 gene therapy in combination with a strong chemotherapy drug in head-and-neck cancers, compared with chemotherapy alone.
Therapeutic Combo
In lung cancer -- the most common cause of cancer-related death in the U.S. -- Introgen is just beginning a midstage test of the use of p53 and radiation together. The company says in its IPO filing that the results are "promising" and will be presented later this month before the American Society of Clinical Oncology.
In trial subject Charles Rogers, 67, the treatment appears to have killed a tumor about the size of a large lemon. "I can tell you I wouldn't be here today without the gene therapy," says Mr. Rogers, a retired insurance agent in Oklahoma. "It saved my life."
Dr. Yver is more cautious. "Normally, radiation alone does do something in these patients, so it's hard to tell which therapy is doing what," he says.
Meanwhile, Schering-Plough has licensed Johns Hopkins's initial patents on p53 therapy from Genzyme Corp., a Cambridge, Mass., company that owns the rights, and has tested p53 treatment in 200 patients in various cancers, with mixed results. In ovarian cancer, it was pleased with the outcome and has launched a final-stage study with patients who have already had surgery.
"There is no such thing as a magic bullet to cause all cancers to go away," says M.D. Anderson's Dr. Clayman. "All cancer treatment is incremental, and so is gene therapy."
Write to Laura Johannes at laura.johannes@wsj.com |
