Health
Cancer Patience
Can an experimental gene therapy effectively treat a malignant brain tumor? Doctors at Houston’s M.D. Anderson are taking it one day at a time.
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Three days later, the Madisons and their daughter showed up at M. D. Anderson and announced that Paul wanted to enter the clinical trial of suicide gene therapy. M. D. Anderson has a worldwide reputation for its expertise in conducting trials, and every year hundreds of patients arrive there seeking access to therapies that aren’t available anywhere else. In 1995 M. D. Anderson administered more than four hundred clinical trials involving nearly 5,300 patients. While some trials are concerned with therapies developed at M. D. Anderson, others are sponsored by research centers or drug companies that want to test new approaches they have developed. The suicide gene therapy trial is an example of the latter: It grew out of work done independently by scientists at the National Institutes of Health and Massachusetts General Hospital. Mass General sold its research to one of the pioneers of gene therapies, a Maryland-based biomedical company called Genetic Therapy, which in turn contacted clinics around the country and asked them to participate in a trial. Doctors at M. D. Anderson were interested because it was a chance to try out a therapy they are likely to use in the future and because it gave their patients an alternative weapon against cancer.
The first patient to receive the suicide gene therapy at M. D. Anderson was 52-year-old Chris Pope. In the spring of 1995 Pope—a Houston Chronicle distributor and an avid outdoorsman—began to feel unusually sluggish. Then he started losing his sense of equilibrium, leading him to speculate that he had an inner ear infection. That May, an ear specialist discovered that Pope could not quickly touch his own nose, or the doctor’s nose, on command. An MRI scan subsequently revealed a large tumor deep in the middle of his brain, and a biopsy revealed that it was a glioblastoma. Because it could not be reached through surgery, Pope immediately began radiation and chemotherapy. By early October, however, the tumor was continuing to grow, and he decided to try the suicide gene therapy. “Chris always had to be the best at everything, so we said, ‘Of course you’d be the first,’” says his wife, Carol. “We decided that even if it didn’t work, there was some meaning, because the doctors could learn more about gene therapy through him. We had no false hopes at all.”
Soon after, Pope was outfitted with a metal halo that guided a needle precisely to his tumor. Through it, Yung’s team injected a retrovirus with DNA from the herpes virus spliced into it. The idea was to infect the tumor’s cells as they replicated, integrating genetic material from the herpes virus into the DNA of the quickly reproducing tumor cells. Then, fifteen days later, Pope was to start intravenous infusions of ganciclovir, an antiviral drug used to treat herpes. The ganciclovir was supposed to mistake the tumor cells for herpes and kill them.
The neat logic of suicide gene therapy—turning the tumor against itself—initially entranced researchers, but like so many new approaches, it doesn’t always work like it is supposed to, and there have been unforeseen side effects. Several days after the surgery, Pope started to feel terribly nauseous and couldn’t eat. Yung was baffled by the reaction until he discovered that the virus had inflamed the membranes surrounding Pope’s brain, causing him to develop chemical meningitis. Once Pope began the infusions of ganciclovir, the nausea cleared up, but he did not survive the glioblastoma. An MRI performed shortly after the therapy was administered indicated that the tumor had continued to grow despite the treatment, and he died on January 13, 1996. Nevertheless, Carol Pope is convinced that it extended her husband’s life. “There is no doubt in my heart that it gave Chris two more months to live,” she says. “In that time, one of our sons got married, the Chronicle presented Chris with an award, and a friend in Atlanta we hadn’t been able to see was able to spend Christmas with us. I look at those two months now and I think how incredible a time it was.”
Curtis Miller, a sixty-year-old oilman from Austin, was the second patient to receive suicide gene therapy at M. D. Anderson. On March 2, 1995, Miller went into convulsions while riding in a car that his daughter Kim was driving. Kim, who is a nurse, first thought he was having a stroke, but she soon realized it was a grand mal seizure. On March 15, after an MRI scan detected a small tumor in Miller’s brain and a biopsy revealed that it was a glioblastoma, a neurosurgeon at Austin’s St. David’s Hospital tried to remove the growth. But as often happens with glioblastomas, the tumor grew back. Miller then went to M. D. Anderson for two rounds of chemotherapy and a second surgery; when they failed to defeat the tumor, he entered the suicide gene therapy trial. “We knew it was experimental, but it’s a hope that you grab onto,” says his wife, Diane. “We were very excited. We felt he had a better than fifty-fifty chance.”
But the gene therapy did not curtail the growth of Miller’s tumor. After an MRI scan revealed that the treatment hadn’t succeeded, Miller underwent surgery for the third time, and it failed too. He died this past August 5. “They don’t know why it didn’t work,” says Diane. “The theory is sound—it’s just so new. But we wanted to help. This kind of cancer is so devouring and so evil; if just one little thing we did helps one other person, it was worth it.”
Last May 2, Paul Madison became the third participant in M. D. Anderson’s gene therapy trial, and his family feared the worst. Several days after the virus was injected into his brain, while they were staying with Alligene’s sister in Houston, Alligene was unable to wake Paul up in the middle of the night to give him a dose of medication. “He couldn’t respond to me at all,” she recalls. “He was just gurgling a little bit—it sounded like he was strangling.” Alligene called an ambulance to rush Paul to M. D. Anderson, where Yung ordered an MRI. The scan showed a broken blood vessel between the skull and his brain; it was causing Paul’s brain to swell to a dangerous degree, and it had quickly sent him into a coma. Still, Yung thought the condition could be treated. “There’s quite a lot of fluid there,” he told Alligene, “but we can fix this.” Paul was rushed into surgery, where the fluid was removed, alleviating the pressure on his brain. The operation was successful, and Paul’s condition stabilized in time for him to begin the infusions of ganciclovir in mid-May.
On June 25 the Madisons returned to M. D. Anderson to see how Paul was responding. “I think it’s time for hugs,” Yung told them: Miraculously, an MRI scan showed no growth in Paul’s tumor. Later, when Paul came back for follow-up tests, the news remained good. Because the tumor has weakened the right side of his body, Paul must rely on a wheelchair or a walker to get around, and he still has a great deal of trouble speaking. The brain doesn’t repair itself, so he will not regain the use of the part that was damaged; however, he is working with a speech therapist to learn to speak using other parts of his brain. These are complications he’s willing to accept, for unlike everyone else who came to M. D. Anderson for the suicide gene therapy, Paul is still alive. In October, when he last saw Yung, he got out of his wheelchair to shake his hand. When Yung told him that the latest MRI scan again showed no signs of growth, he was so relieved that he started to cry.
The Madisons want everybody to know about their experience so that others can benefit from gene therapy. “This needs to be told,” says Alligene. “We hope to enlighten other people.” But of course, it’s important to remember that the therapy appears to have helped only one out of three patients at M. D. Anderson. “This is our frustration—not all tumors react the same way,” Yung says. While he considers a survival rate of 33 percent surprisingly good for glioblastoma, he does not yet share Alligene’s unabashed enthusiasm for the new treatment. “The important thing with gene therapy is not to oversell it,” he says. “Patients think it is going to be their salvation, and when they don’t get the results they are waiting for, they are very disappointed. There are a lot of problems we need to solve before we can call this a good or an excellent treatment.”
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