Going in: Sampson performs a craniotomy on a patient who's awake, to avoid damaging nerve and speech centers.   Chris Hildreth
Going in: Sampson performs a craniotomy on a patient who's awake, to avoid damaging nerve and speech centers. Chris Hildreth

Mind Over Matter

Neurosurgeon John Sampson is among the pioneers working on a vaccine that harnesses the body's immune system to fight deadly brain tumors, offering hope where there was none.
August 1, 2008

On the third floor of Duke North in Operating Room 4, neurosurgeon John Sampson is using what looks like a blunt, two-pronged fork to probe sections of a patient's exposed brain. Weeks earlier, an MRI had revealed a shadow near the front of the man's skull, an ominous intruder whose appearance on the black-and-white scan resembled a satellite view of an advancing hurricane. Sampson suspects a high-grade tumor, possibly a glioblastoma multiforme—the most common and deadliest form of brain cancer.

The tumor had been growing stealthily in the patient's head until, one day in April, the sixty-eight-year-old man sat down, exhausted, and could not get up. A flurry of medical tests and phone calls later, he is now at Duke Medical Center, in the hands of one of the top brain tumor surgeons in the world.

Because the growth is pushing against the left frontal lobe in an area that controls speech and facial expressions, Sampson is performing a craniotomy while the patient is awake, slowly and methodically cutting his way deeper and deeper into the brain. Throughout the three-hour operation, Sampson will rely on the patient's responses to cues to help guide catheters, aspirators, and three-dimensional imaging tools to target the spot where the burrowing tumor resides.

Under the layers and layers of surgical drapes that cover the patient, nurse practitioner Denise Lally-Goss huddles close to the man's face, talking gently. To the rest of the OR team, the voices are muffled, barely discernible. She holds up flash cards and prompts the man to identify what images are pictured.

"This is a…" says Lally-Goss.

"Frog," the man says.

"This is a…"

"Comb."

Through a hole in the patient's skull roughly the size of a computer mouse, Sampson and his surgical assistant are mapping out safe entry points through the brain's dura mater to get to the interior of the delicate frontal lobe. It's as if Sampson is in a house he knows like the back of his hand, but it's night, and all the electricity has gone off. The man's responses are like a dime-store flashlight, pointing Sampson toward safe passage, or warning him away from danger.

Then the patient starts missing cards.

"Two out of five," Lally-Goss calls out to Sampson.

And then, "Okay, he missed all five."

"Get him to count to ten," says Sampson.

No response.

Like a thunderclap, Sampson bellows the patient's name, commanding all the energy and attention in the beeping, humming operating room. "We need you to be loud. Tell me what's on the cards. This is a…"

"Chair!" exclaims the man, correctly.

"This is a…"

"Rabbit!"

"This is a…"

"Fork!"

Back on track. Sampson gently chides Lally-Goss. "Denise, this is no time to be using your indoor voice. I need you to really get in his face and keep him focused."

Two hours into the operation, Sampson has isolated the tumor, a white spongy contrast to the vibrant deep pink of its host. After the meticulous precision used to cut around the cancerous area, its removal is surprisingly quick. A section of the golf-ball-sized growth is whisked to the lab for analysis. Sampson and his colleagues use an ultrasound wand to scan the brain for residual tumor, then begin the process of closing up the groggy patient's head.

The initial lab analysis indicates what later tests confirm: a grade IV glioblastoma multiforme, a highly malignant, fast-growing cancer for which there is no cure. Most recur within six months. The vast majority of patients are dead within eighteen months.

Every year, between 10,000 and 20,000 people in the U.S. are diagnosed with glioblastoma multiforme (GBM) tumors. No one knows what causes them. They are primary tumors, meaning that they begin in the brain rather than metastasizing from somewhere else in the body. GBMs are insidious. They send tentacles into the brain, becoming inextricably wrapped around healthy tissue; even though neurosurgeons can remove what appears to be the bulk of the tumor, virulent cancer cells are invariably left behind. The usual course of treatment is removal (when possible), followed by radiation and chemotherapy. This standard of care has not changed significantly in nearly fifty years.

A native of Canada, John Sampson was recruited straight out of medical school at the University of Manitoba to join Duke Medical Center's neurosurgery residency program in 1990, and he's been here ever since. He sometimes tells people that he briefly considered becoming a general practitioner because he liked the idea of forging lifelong relationships with patients. But it's hard to imagine Sampson, or any of his colleagues at the Preston Robert Tisch Brain Tumor Center, for that matter, content with performing routine physicals and annual check-ups. Brain surgeons tend to be mavericks, tireless and intensely driven, offering patients the promise of hope when other doctors have exhausted all options.

Malignant Intruder: MRI reveals stealthily growing tumor.

 

Chris Hildreth

Early in his residency, Sampson knew that mastering complex surgical challenges wouldn't satisfy him over the long haul. Performing delicate brain surgery was one thing, but understanding the pathology of brain tumors—and perhaps unlocking the mystery of what causes them in order to better treat them—was quite another. He took three years out of his residency to work alongside Darell Bigner M.D. '65, Ph.D. '72, an internationally known expert on brain tumors, earning a Ph.D. in tumor immunology and learning how to design and conduct clinical trials.

Since then, Sampson and his colleagues at the brain tumor clinic have helped pioneer the use of immunotherapy—he calls it "the holy grail of therapy"—which uses the body's immune system to fight cancers like GBM. "Chemotherapy and radiation are systemic rather than specific," Sampson says, "so they kill the good cells along with the bad cells. But immunotherapy is very specific. It targets only the tumor cell, and leaves healthy cells untouched."

Through painstaking trial and error, Sampson and fellow researchers developed a vaccine that slowed the reappearance of GBM-specific tumor cells in mice. By 2001, he had received National Institutes of Health funding and approvals to conduct clinical trials in humans. There were no guarantees that it would work; patients who agreed to enter the trials knew that it was risky, unproven. It could be ineffective. It could make the tumor come back even stronger. Or maybe, just maybe, it could buy them more time.

Two days after the craniotomy in Operating Room 4, Cam and Peggy Mitchell fly in to Raleigh-Durham International Airport for their monthly trip to Duke Medical Center. The two have known each other since childhood; her sister sat behind Cam in first grade. Cam was diagnosed in 2004 with a grade IV GBM. His doctor in Grand Rapids, Michigan, gave Mitchell a pamphlet about GBM and told him, "Sorry, there's nothing we can do."

Mitchell's oncologist, though, knew about the research being conducted at Duke. He made a few calls. On a Saturday morning, about a week after his diagnosis, Mitchell's phone rang. It was John Sampson, calling from his home. Mitchell could hear Sampson's two young sons playing in the background. Sampson explained that he was starting to enroll human subjects in an experimental clinical trial.

Was Mitchell interested?

"When you're first given the news that you have a stage-four brain tumor, you really don't expect to survive," says Mitchell. Faced with the prospect of certain rapid decline or the slim hope that he might live a few months longer to see his beloved brood of nieces and nephews pass the next birthday or kindergarten graduation, Mitchell didn't hesitate. "People have told me that they would never want to be a guinea pig, but I don't see it that way. I thought, Hey, I've got to be willing to try something leading-edge. Someone has to be willing, and I'm going to be that person."

"The new normal": Cam Mitchell undergoes blood work and lab tests
every month before receiving the life-extending vaccine.

 

Butch Usery

In June of 2004, the Mitchells and nearly twenty members of their extended family traveled to Duke to support Cam as he underwent a series of tests to determine whether he qualified for the trial. Trial parameters included, among other factors, how recently the tumor was diagnosed and removed, its size, and whether it contained a specific protein, found on fewer than half of GBMs, that the vaccine was designed to target. When the tests came back confirming that he was a good candidate, "I felt as though I'd been given a lifeline," he says.

Four years later, the Mitchells have come to consider Duke a second home. They've negotiated medical discounts with airlines and hotels, can tell you which food station in the hospital cafeteria makes the healthiest turkey sandwiches, and know that the local Nordstrom can hem a pair of pants in one business day. And they are on a first-name basis with the dozens of physicians, nurses, and support staff members who oversee Cam's health.

On this particular spring trip, Mitchell receives his forty-eighth dose of vaccine. He's brought a CD containing scans of his latest MRI, conducted bimonthly in Grand Rapids, for Sampson to examine for signs that the tumor has started to grow again. Waiting for the results is agonizing. "My mind starts to begin this circle of thought," says Mitchell. "What if I have a recurrence? What if the test is inconclusive? What if the radiologist misses something? Everything related to my treatment is so new that there are no 'norms' to rely on."

Later that afternoon, Mitchell gets the good news that the tumor has not returned. Not this month. Not today. It's a small, temporary reprieve between the exhilaration and dread that have become, in Peggy's words, "the new normal."

Cancer occurs when cells mutate. In some, but not all, GBMs, these mutations take place on the epidermal growth factor receptor (EGFR) of the tumor's surface cells. The mutation, known as EGFRvIII, was discovered by Duke's Darell Bigner and his cancer-research colleagues at the Johns Hopkins University who conduct GBM research. EGFRvIII has also been implicated in a range of other cancers, including breast, ovarian, metastatic prostate, colorectal, and head and neck cancers.

The brain tumor vaccine, which consists of a slightly modified portion of EGFRvIII, triggers the immune system into attacking just those cancer cells. Called CDX-110 and manufactured by AVANT Immunotherapies, the vaccine was developed by Sampson and Amy Heimberger, who completed her internship and residency at Duke. She is now an associate professor at the University of Texas' M.D. Anderson Cancer Center and the lead investigator for a concurrent brain tumor vaccine trial at Texas. "The vaccine works with exquisite specificity," says Sampson. "It's like a silver bullet."

In clinic: Sampson and Duke colleagues offer patients hope when other doctors have exhausted all options.

 

Chris Hildreth

Before enrolling in the clinical trial, and on subsequent visits to Duke, patients must undergo a series of tests to make sure the tumor hasn't started growing back. For the first two months, the vaccine is administered every two weeks, and then monthly as long as there are no signs of recurrence. The only side effects are slight swelling or redness near the injection site.

Because of the virulent nature of GBMs, physicians are accustomed to seeing them recur within months. In the clinical trials, Sampson says, the average recurrence is pushed out to nearly two years. Even more remarkable, "We now have patients who are three and four years out with no recurrence," he says.

When the trials started in 2004, patients received the vaccine alone. More recently, Sampson wanted to know what might happen if the vaccine was used in conjunction with temozolomide, the standard chemotherapy drug given to brain tumor patients. "The problem with temozolomide is that, like any chemotherapy, it kills off cells indiscriminately," says Sampson. "Our hypothesis was that using the temozolomide would kill so many white blood cells that it would essentially cancel out the benefit of the vaccine." As it turned out, using temozolomide enhanced the immune system tremendously, and in fact, the higher the dose, the better the body's overall immune response.

"We're now seeing patients who not only achieve very high immune responses over time, but whose immune responses just get stronger and stronger and stronger—to the point where we're seeing [immune] levels not typically seen with any vaccine," says Sampson. "It's unusual in nature that an immune response gets stronger and stronger. But that has been the case with this therapy."

So far, over 70 percent of patients who have enrolled in the vaccine trials at Duke are alive after two years, and over 50 percent are alive after four years.

 

Source: John Sampson

Ryan DeGrand is among the fortunate 50 percent. A self-described Type-A personality, he ran 5K races in and around his hometown of St. Louis and routinely worked fifteen-hour days as the vice president of ProAm Golf, a golf equipment company founded by his father in 1975.

In 2004, at the age of thirty-two, he developed crushing headaches that didn't respond to over-the-counter medicine. Finally, unable to stand the pain, DeGrand went to a local emergency room, where a CT scan revealed a baseball-sized tumor—a GBM. With a four-year-old son and a newborn daughter at home, he and his wife, Kathryn, were suddenly faced with the unthinkable.

"I played sports all my life. I never smoked. I eat well and work out at least twice a week, so there was no way in my mind that I could get cancer," says DeGrand. With the same drive he brought to other areas of his life, DeGrand refused to believe the doctors who told him there was nothing that could be done. "I remember walking to my car that day and thinking, those are the most negative guys I've never met, and I'm not going to listen to them." DeGrand researched his options, and quickly honed in on the trials at Anderson Cancer Center and Duke. He flew to Durham to meet with Sampson and see whether he qualified for the clinical trials. He did, and in August of 2004, he began getting the vaccine.

"What I like about the vaccine is that it's making my body stronger," says DeGrand. "It's boosting my immune system and making it healthier, as opposed to chemo, which weakens your whole system. It's also why I like Duke; instead of being on the defensive and waiting to treat the next bad thing that happens, they are always looking at ways to improve the treatment and make it even better."

DeGrand, like Mitchell, is often asked how much longer he plans to come back to Duke. "Why would I stop?" he says. "As long as my immune system keeps getting stronger and the tumor doesn't come back, I'll keep getting the vaccine. I hope I'm still coming back here in twenty-five or thirty years."

Still, DeGrand acknowledges that he and his wife can't allow themselves to imagine what their lives will be like a year from now, much less a couple of decades hence. "I really try to take one day at a time," he says. "If I start to forecast things that might happen six or eight months from now, I can fool myself into thinking that I'm beating the deal. We talk hypothetically about taking a trip with the kids at Christmas. But realistically, we can't start making those plans until September or October."

In late April, ABC News' World News Tonight aired a short segment on DeGrand and his treatment at Duke. In the days that followed, Sampson's office was deluged with hundreds of e-mail messages and phone calls from people all over the world who had seen or heard about the vaccine. Could they, or a loved one, get in?

Nurse practitioner Lally-Goss and a clinical trials coordinator triaged the calls, responding to every single one within forty-eight hours. Most patients did not qualify for the vaccine. For Sampson and others on the front line of treating people with GBMs, fielding desperate queries from people who have no other hope further galvanizes them in their quest to stop this deadly disease.

"This is not a cure," says Sampson. "But it's one really good step in that direction."

A few weeks after the craniotomy described in the lead of this article, the patient's tumor recurred, making him ineligible for clinical trials. He will continue to receive the standard treatment of radiation and chemotherapy.