A Six-Foot Lab Rat

Samuel Hassenbusch knows brain tumors. As a neurosurgeon at M.D. Anderson Cancer Center in Houston, he's been operating on them since 1988. But early last year, when he suffered a month long string of persistent headaches, he told himself it was just stress. After all, he was only 51 and fit enough that he'd just completed a charity race for his hospital, combining a 5K run with a 50-mile motorcycle ride--or, as he calls it, "the iron-leg and iron-butt competition." When the thought kept popping into his head that he might have a brain tumor, he quickly dismissed it. "Come on, this is paranoid," he told himself. "Get an MRI to prove it's nothing." Hassenbusch went for the scan on May 10, 2005. When he exited the scanner room, he saw a 17-by-14-inch film posted against a light board--probably some other patient's. Poor guy. Even from 10 feet away, Hassenbusch could see clearly that the patient had a large glioblastoma--the deadliest type of brain tumor. He moved in for a closer look. That's when he saw the name on the top in small white letters--Hassenbusch, Samuel J.

In an instant he knew exactly what the next year of his life was going to be like, and it wasn't pretty. "Only 3 percent of glioblastoma patients survive five years--and that's the good news," he says. "More than two thirds die in a year, according to the Central Brain Tumor Registry." Twenty years of medical advances have done little to alter that. But for the first time in decades, scientists are now daring to hope that a series of experimental new therapies could one day meaningfully extend patients' lives--not by weeks, but by months and even years. Hassenbusch became the first person in the country to receive one of them. And though it is too early to declare that he's in remission, he says, "So far it seems to be working. I'm 18 months out, and the tumor hasn't recurred."

That he can make that statement at all is no small feat. Glioblastomas are among the most lethal tumors, because they are resistant to both chemotherapy and radiation. Worse, they send out microscopic tentacles that seed other areas of the brain with individual tumor cells. Even if a surgeon can remove the main mass of a tumor, he cannot possibly excise all these scattered cells. It would be like a chef trying to remove the marbling from a marble cake--and get every last crumb. These additional cells generate new malignancies, sometimes within weeks of the initial operation.

Knowing all that, hassenbusch underwent surgery at M.D. Anderson on May 25, 2005. He followed up with radiation and chemotherapy. But he had no intention of stopping there. Heck, he was at one of the nation's premier facilities for cancer research, and he was going to look into every possibility. "I made myself into a six-foot-tall lab rat," he says.

After combing the medical literature, he approached Dr. Amy Heimberger, a fellow neurosurgeon at M.D. Anderson, and asked about receiving a new treatment she was testing with Dr. John Sampson at Duke--a cancer vaccine for glioblastoma. The vaccine works by training the immune system to attack cells that have an abnormal receptor on their surface called (take a deep breath) epidermal growth factor receptor variant III, or EGFRvIII. This receptor is found on almost half of glioblastomas and is one of the things that jack up growth signals in them. In phase-two testing, the vaccine has extended patients' median survival to at least 29 months. But the vaccine works only if one's tumor cells carry that specific receptor. Hassenbusch's did.

But he wasn't content to receive the vaccine alone. He wanted the vaccine plus chemotherapy. The conventional wisdom is that the two are incompatible, since chemo destroys the immune system's white cells--the very thing that a vaccine is supposed to unleash against the cancer. But Sampson had discovered in lab mice that if one waited until white-cell counts bounced back after chemo, then the vaccine could be even more effective in combination with chemotherapy than on its own. "The question was, could we do for Sam what Dr. Sampson had done for those cute little mice?" says Heimberger. Hassenbusch was willing to try--and he became the first person in the country to receive the two treatments on an alternating schedule. He calls it his "double whammy--a one-two punch against the disease."

Hassenbusch may be lucky in another way (if one can call any cancer patient lucky). His cancer appears to be especial-ly responsive to the new chemo drug Temodar, which he's taking as part of his dual therapy. Many patients gain only 2.5 months or so of added survival time from Temodar, because they have a gene that repairs tumor cells almost as fast as the drug can injure them. But that gene is inactive in about 40 percent of patients, who tend to do better. Hassenbusch is among them. Though he is unusual in that he is in the subset of patients who seem to gain the most from Temodar--and who will benefit at all from the vaccine--Heimberger foresees the day when there will be vaccines for all glioblastomas. "There are a dozen other [proteins] that are found only on glioblastomas that could be targeted with vaccines," she says. "One day we will be able to test a patient's tumor cells for these and deliver tailor-made treatments."

Long before that day arrives, another drug seems poised to make it to market. Dr. Sandeep Kunwar, a neurosurgeon at the University of California, San Francisco, is working with a drug called IL13-PE38, which is already in phase-three testing. As its hyphenated name implies, it is a two-part drug. The first component--interleukin 13, or IL13--is a naturally occurring immune-system compound. As it turns out, the vast majority of glioblastomas have high levels of receptors for it, but normal brain cells have none. That means that when the drug is injected directly into the brain, it seeks out the tumor cells and binds to their IL13 receptors. (The blood-brain barrier keeps the drug from migrating to other parts of the body that also have these receptors.) The IL13 then serves as a sort of Trojan horse that allows the deadly part of the drug--PE38, a toxin produced by pseudomonas bacteria--to slip inside the tumor cell. "PE38 is a nature-designed killing enzyme," says Kunwar. "It's far more efficient at killing tumor cells than typical chemotherapy." In phase-one testing, 20 percent of patients who received a particular variation of this treatment were still alive three years later, which is "almost unheard of," he says.

A few patients have done even better. Among them is David Herbert, 64, of Lincoln, Calif., who is still alive six years after receiving his cancer diagnosis on Dec. 5, 2000. "I'm the poster boy for this drug," he admits. He was also the first recipient of IL13-PE38. But the fact that no other patient had tried it before him didn't make him shy away. "I still had a lot to live for," he says. "Whatever it took, I was going to get through this." Without it, he would likely never have seen his 2-year-old granddaughter, Hope, who was indirectly named for him. Sadly, in August his tumor came back, which he found deeply discouraging. "This isn't a cure," warns Kunwar. "But with just one treatment, we are doubling patient survival." He expects to finish the phase-three trial in early 2007 and, if the results are favorable, have FDA approval within a year.

In principle, at least, there are other intriguing approaches. "In some rare cases, people with a viral infection have spontaneous remissions from other types of cancer," says Dr. Juan Fueyo, associate professor of neuro-oncology at M.D. Anderson. "That raises the question, can vi-ruses help fight brain tumors?" Together with his wife, Dr. Candelaria Gomez-Manzano, Fueyo is testing a virus known as Delta-24-RGD that seeks out brain-tumor stem cells. The specially engineered virus infiltrates these cells, then replicates and destroys them. But here's the beauty of the virus. It's incapable of replicating in normal cells, because they have a protein that blocks it. So far, Delta-24-RGD has been tested only in mice, but the results were dazzling. When Fueyo examined the animals' brain tissue, he says, "there was no tumor left--just empty cavities and scar tissue where the tumor had been."

As for Hassenbusch, he's back on the job--and has even taken on additional responsibilities. "I could sit with fuzzy slippers on the La-Z-Boy and watch 'Judge Judy'," he says. "But I guess I'm too dumb to know I should be sick." He's even performing surgery, although he tells patients during their initial consultation that he's had a brain tumor, in case they want another surgeon. So far, no one has--and, in fact, his own experience has made him far more empathetic toward his patients. Even if things don't work out for him in the long run--and the statistics suggest they won't--he says he will have contributed to science. But he's not dwelling on that. Instead he's planning for May 10, 2010, the day that he hopes will mark his five-year survival. He will have a repeat brain scan (like the ones he has every month to monitor his condition), and if the results come back clean, he says, "I will run outside, look up and shout at the top of my lungs, 'Thank you!' " He pauses a moment. "Well, I don't know if I'll actually shout," he says. "But there will be a lot of 'Thank you's." And that could potentially spell hope for a lot of people with a hopeless disease.

A Six-Foot Lab Rat | News