27 Jul 2013
What’s your full name?
Where are you?
What month is it?
What day of the week is it?
Walter Keller tried to speak, but no words came out, only a dry rasp. The man asking the questions had dark, close-cropped gray hair and a kind, level gaze.
Eventually the man left the room. Walt wriggled up in his bed. Someone put a hand on his shoulder and pressed him gently back into the mattress.
Walt—tall and rawboned, with marbly green eyes and muscles hardened by a lifetime of physical labor—tried to elevate himself. An earsplitting noise went off. A nurse came running in and told him to get back down. When she left, Walt found that the nurses had clipped an alarm to his bed that would alert them whenever he tried to get up. He ripped it off and threw it to the ground.
The man was back:
What’s your full name?
Where are you?
What month is it?
What day of the week is it?
Walt had to get out of this room. He had a baseball game to coach, over at the ball field in Upland, California. The Upland Pony Giants were waiting for him. Michael was waiting, the skinny kid with the cannon arm, and Cody, the kid who could steal two bases on one pitch. The game was starting in five minutes—didn’t anyone understand that?
Walt glanced to his side and saw his 19-year-old son, Dustin. Dustin was here, thank God. Dustin would listen.
“Dustin, get my shoes,” Walt croaked. “Dustin, I have to get out of here. I’ll give you a ride on the boat.”
Walt knew his boat was right outside the door of the room—the wakeboard boat he drove every year up and down Lake Mohave in Nevada, giving water-ski rides to his grandkids. His boat was right here at the hospital. If he could only make it out of the bed, to the door, he could climb into the boat and drive it back to his house.
Dustin shook his head: broad shoulders, soft voice, cherubic face, dark brown hair.
“Dustin,” Walt said, eyes soaked with confusion, “you are infuriating me.”
Walt wasn’t in California, as he thought. He was 2,700 miles east, in Philadelphia, where he’d come to be a guinea pig in a test of a new kind of cancer treatment. Leukemia had invaded his bone marrow and spread like a stain through his lymph nodes; the traditional options, including chemo and radiation, had failed. He was 58, and his body groaned with tumors potentially weighing as much as seven pounds. Walt needed something radically different if he was going to live. And the treatment he’d been given a few days ago was certainly that.
Over the past several years, a couple of hundred mice had received it, but Walt was only the seventh adult human. (Six men had preceded him, as well as a six-year-old girl.) The treatment wasn’t a chemo drug, and it wasn’t a vaccine. Instead, doctors at the University of Pennsylvania had tried to make Walt’s own body the drug. In an approach known as gene therapy, they’d taken his own immune cells, modified them to give them new powers, and injected them back into his blood.
Gene therapy represents a break from the medical past. Like open-heart surgery, antibiotics and low-cost medical imaging, it’s a “disruptive” technology capable of changing the way doctors do business. It could transform how we treat many types of cancers in people of all ages—if it can be made to work. But that’s the problem. Before this trial at Penn—a Phase 1 trial, the earliest possible human test of a new treatment—gene therapy had scarcely worked in cancer, anywhere in the world. A typical gene-therapy experiment in cancer was as exciting as a sip of warm tea. Nothing happened, good or bad. In other kinds of gene-therapy trials, there had been tragedies: At Penn in 1999, in a trial run by doctors unrelated to the team treating Walt, a teenager with an inherited liver disease had died after a gene-therapy infusion sparked a runaway reaction.
But Walt’s doctors had done things differently than past scientists. Their approach was original and new. And, incredibly, they’d already succeeded in making tumors vanish in a few of the patients who’d come before Walt. Using their custom technology, the Penn physicians had jolted two cancer-riddled men into sudden apparent remission—an outcome dramatic enough to earn mentions on TV news and a write-up in the New York Times. In September 2011, the paper described Penn’s work as “a turning point in the long struggle to develop effective gene therapies against cancer.”
But now, eight months later, at the Hospital of the University of Pennsylvania, something dramatic was happening inside Walter Keller’s body—a riot of cells and signals. His blood pressure had crashed, so doctors had pumped him full of fluid to raise it, and the fluid had blown up his neck like a balloon. Socks were wrapped around his bloated legs to help with blood circulation. His kidneys were failing. He shook at times with “the rigors,” excruciating full-body shivers that made his whole body feel the way his heart would if he had just run up a huge hill.
Scientists don’t talk about “curing” cancer. A cure is the hope so great, so seemingly out of reach, that it must never be invoked. They’ve built a wall around the word. Still, the Penn researchers—as careful as they were, as professionally sober and skeptical—couldn’t help but wonder: Was their small experiment the start of something that could one day affect thousands, tens of thousands, more? Was it revealing a secret about the human body that could point the way to treatments for other cancers, not just leukemia? There was no way to know until they gathered more data. They needed to show that the therapy was safe. And they needed to prove that the early patients—the men whose tumors they’d blasted away—weren’t flukes.
Which is why so much now depended on Walter Keller. If Walt’s condition improved and his tumors diminished, the trial would move forward, and the potential of the Penn therapy—the result of a decades-long quest of scientific passion and discovery—would continue to grow. But if he suffered harm, Penn would have to pause the trial and maybe stop it altogether. Then everything would spiral down. Other scientists would argue that gene therapy was a dead end. Funding would dry up; research would wither. The Penn doctors might never get another chance to prove the merits of their idea, and we might all lose out. It had taken 20 years to get to this point, and it could all be over in the space of a few moments.
1996, Bethesda, Maryland
Captain Carl June had a way of making science seem almost mischievous—something in the curl of his lip, the folding of his hands in his lap. He was an intense character even by the standards of the U.S. Navy medical community, which tended to attract driven personalities. He’d played football as a younger man. He was 42 now and ran ultra-marathons; his calves were like titanium rods.
He directed a research lab on a Navy medical campus. The main goal of his lab was to make the human immune system do things it hadn’t evolved to do. Improve it. “Put it on steroids,” he liked to say.
June had a tinkerer’s temperament, a fascination with inventing tools to make new kinds of inventions possible. Some of this he had absorbed from his father, a chemical engineer in the San Francisco Bay area. As a kid, June planned to go into science, but then the Vietnam War came, he enlisted in 1971 and received a congressional appointment to Annapolis. He trained for a time as a sailor on a nuclear sub. “Very cool technology,” June would later recall. “And then the war was over, so they said, ‘You don’t have to do this stuff. You can go to medical school.’ So I did that, and it was cool.” After med school, the Navy sent June to Seattle to learn how to perform bone-marrow transplants. If there ever was a radiation leak on a sub, the Navy would need doctors to give the sailors new immune systems, which is essentially what a bone-marrow transplant does. The procedure saves lives, but at considerable risk; it’s estimated to kill one in five. June saw heroic transformations as well as tragic deaths.
Now, in his Bethesda lab, June mostly studied HIV, the virus that causes AIDS. It was another lens for looking at the immune system, its powers and limitations. HIV is so insidious because it infects the very immune cells, called “T cells,” that would normally kill it. June wanted to know everything about T cells. But it was hard to study them, because it was hard to grow them in the lab. So June created a better way. Working with a quiet, meticulous researcher named Bruce Levine, June discovered that he could coat artificial beads with proteins that mimicked the natural cells that normally coax T cells to divide. The beads, round and about half the size of a cell, were made partly of iron; when you wanted to use the T cells that had grown, you just passed the cells and beads over a magnet. The beads got stuck on the magnet, and the cells flowed through.
June enjoyed his work at the Navy, and peers across the country respected his creativity—“a real genius,” Laurence Cooper, an immunologist at the University of Texas MD Anderson Cancer Center, calls him—but by 1996, he’d begun to feel restless. The Navy only funded research into infectious diseases like HIV, and he wanted to study cancer. His wife, Cynthia, had recently been diagnosed with ovarian cancer. They had three kids in high school and college. June wanted to use what he’d learned about the immune system to tackle the disease. And more than that, he wanted to find a way to get his ideas out of the lab and into the wider world of suffering and need.
June retired from the Navy in 1996. For the next three years, he continued working in the same lab as a civilian, employed by a foundation, while caring for his wife as she endured chemo. “I learned a lot about being on the other side of a bed,” June says, “and what it’s like going through the ups and downs of cancer therapy. I had no idea of the impact.”
In 1999, Penn offered June a prestigious appointment at its medical school. It was the chance he’d been waiting for. He moved to Philly, bringing Levine with him, and launched a new lab to translate basic science into drugs that could be commercialized, including cancer drugs. Meanwhile, Levine began to build a pilot facility that could produce drugs and vaccines in small batches: the Clinical Cell and Vaccine Production Facility. It was like a biotech company in miniature. In 2005, Levine scaled it up, moving into a warren of renovated lab space in a hospital building off Spruce Street.
Some of its first creations were custom cancer vaccines for the benefit of June’s wife. “She wanted to go for the home run,” June recalls. She wanted to see her kids grow up. He was sympathetic, of course; in her place, he’d have wanted the same. But in talking to some of his colleagues about risk, June came to realize that not everyone would. “Some people are not risk-takers at all,” he says. For the first time in his career, June was forced to think about what it really meant, on a human level, to become a guinea pig in a cutting-edge medical trial—or to turn down that chance. What’s more rational? To fight, or to accept your fate with grace?
The vaccines didn’t work well enough to save Cynthia June. After five years of treatment, including two bone-marrow transplants, she died in 2001.
1996, Upland, California
Robin was on the phone. She was down at nearby Ralphs supermarket, where she worked checkout. The union had brought one of those mobile health vans to the store. Walt should come get a physical exam, she said. Why not? It was free.
To humor his wife, Walt drove to Ralphs and climbed into the van. He gave a sample of his blood. A few days later, he picked up the phone. “There’s something wrong with your blood,” a voice said. “We’re praying for you.”
Leukemia. Walt, it turned out, had the most common type: chronic lymphocytic leukemia, or CLL. Walt had always worried he might get cancer one day—his father had died of non-Hodgkin’s lymphoma, and Walt had spent decades sucking down wood-stain fumes in his job as a cabinet refinisher—but still, the diagnosis felt like an ambush. At 43, he was scared of losing everything he’d built. He’d come so far from the little house in neighboring Montclair, where he’d grown up poor and afraid.
One day when Walt was 14, his stepfather burst through the door, carrying a gun. He told Walt not to move. He grabbed Walt’s mother around the waist and pushed her out into the side yard. Walt heard a gunshot, then two more. He went into the yard. His stepfather and mother were both splayed out on the ground. The man had shot her, then shot himself. Walt stood there in shock. His mother was bleeding from her nose and ears. He went back into the house, got a pillow from his room, and put it under her head.
After the murder-suicide, Walt’s birth father moved back in. An alcoholic painting contractor, he was too drunk to work. He made Walt ride his bicycle to the liquor store to fetch whiskey. The eldest boy of six siblings, Walt had to drop out of school at age 16 to support his brothers and sisters.
So his current prosperity, 30 years later, struck him as faintly miraculous. Two grown daughters, Chelle and Shawna. A three-year-old son, Dustin, whose birth had leveled him with a joy so intense, he didn’t know what he’d done to deserve it. A spacious house with a courtyard and palm trees in Upland, just 15 minutes from Montclair but a world away, where Walt ran his own cabinet business and coached youth baseball. Walt wanted to see Dustin grow up; he wanted to see Chelle and Shawna start families of their own. He told his oncologist, Linda Bosserman, that he’d try anything.
After monitoring his cancer for two years, Bosserman started Walt on chemo in 1998. Up to three times a week, three weeks a month, Walt sat in a recliner as poison poured into him. One day he came home from a chemo treatment and Dustin was there, looking up at him. Dustin’s dark brown hair was only thickening as Walt’s was falling out. “Dad,” he said, “if you die, how am I going to talk to you?”
The chemo was preparation for a course of full-body radiation, which crisped Walt’s skin and left his mouth so full of blisters that he needed morphine to dull the pain. After that came a stem-cell transplant, a procedure in which blood is drawn from the body and spun in a centrifuge to extract pure stem cells, which can generate new, healthy bone marrow cells. Then, after chemo and radiation wipe out the bulk of the cancer, the stem cells are injected back into the veins.
The stem-cell transplant, in 1999, bought Walt five and a half years of remission. He built a rudimentary batting cage in his backyard and worked with Dustin there, sitting on an overturned milk crate in the cage and tossing his son dozens of underhanded pitches. When the cancer returned, in 2005, Walt went through the whole procedure again: more chemo, more radiation, a second stem-cell transplant. “That’s like going to hell twice,” he says.
It worked, until it didn’t.
In 2010, when Walt was just shy of 57, he began to feel abnormally tired and weak. He knew what it meant. Eventually he went in for some blood work. The next time he saw Dr. Bosserman, in August, she spoke to Walt in a tone he’d never heard before.
His cancer was back again. And there were no good options left. A third stem-cell transplant wasn’t in the cards. None of his family members were a genetic match for a bone-marrow transplant. All Walt could do was place himself on a waiting list to receive a transplant from a stranger. In the meantime, Bosserman would start him on a third course of chemo and hope for the best.
Almost immediately after starting on the drugs, Walt sensed that he had reached the end.
Meanwhile, his sandy-haired daughter Chelle, a birthing consultant at a local hospital, started talking to him about heaven. She had a family of her own now, and was raising her children to know Jesus. “Heaven is real,” she’d say, “and we know how to get there. We’ll see each other again.”
Walt had never been much for church. But he thought about his love for his daughter, that feeling so powerful you can’t put it into words, and he thought about how God knows when you’re low and what’s in your heart, and suddenly it all made sense: He is using my love for my daughter to reach me. He is using Chelle as a vehicle.
He tried not to be afraid. He climbed into his van every day and went to work. In the van, he listened to Vin Scully call the Dodgers games on the radio, marveling at how Vinny could make you see the action in your head: every pitch, every hit and stolen base, a game of seemingly infinite complexity mastered and mapped.
One day, Walt was finishing up some French doors by the pool of a client when the man of the house rushed out, eyes aflame. “Walt, Walt,” the man said, “there’s a lady on TV, and they say they have a cure for what you have.”
“Ah, there’s no cure for what I have,” Walt mumbled, and went back to work.
When he got home that night, he turned on the evening news. The newscaster started talking about leukemia.
Walt’s cell phone lit up.
T cells. Carl June had an idea for a new kind of cancer treatment involving T cells, those building blocks of the immune system.
In their natural state, T cells usually aren’t able to kill tumor cells, partly because they can’t latch on strongly enough. But June was fascinated by scientific papers showing it was possible to change this. A few researchers—first an Israeli named Zelig Eshhar in the ’80s, then other investigators around the world—had discovered that you could force a T cell to stick to a tumor cell and kill it. To pull this off, you built an “engineered T cell”—a T cell never before seen in nature. You altered the T cell’s genetic blueprint by injecting a new gene into the cell. The new gene would tell it to build a new molecular limb. The limb, called a “chimeric antigen receptor,” would sit partly inside the cell and partly outside, and it could send signals either in or out. One signal it could send was: kill. Another was: replicate.
June loved this approach. So elegant. Put the immune system on steroids. What if you could train the body to fight cancer on its own? What if, instead of replacing a patient’s immune system (as in a bone-marrow transplant) or pumping him full of poison (chemo), you could just borrow some cells, tweak them, and infuse them back into the patient? In theory, the engineered cells would stay alive in the blood, replenishing themselves, killing any tumors that recurred. It occurred to June that one infusion could last a lifetime.
He was also excited by the flexibility of engineered T cells. Normally, a drug for one kind of cancer couldn’t ever work on another kind; you had to start over from scratch. But here, since you were starting with a T cell and adding a limb, you only had to change the shape of the limb. You could snap a new piece on the end, like a LEGO, that fit into a molecule on the surface of a breast-cancer cell, or a pancreatic-cancer cell, or whatever kind of cancer you wanted to attack.
June and Levine had actually tested engineered T cells before, in patients with HIV. The cells hadn’t cured anyone, though they did improve immune-system function. But June wondered if the cells could work in cancer. Around 2003, he started discussing a cancer trial with a few colleagues at Penn, including Levine and an oncologist, David Porter. Porter ran the bone-marrow transplant program at Penn, and he was passionate about investigating new treatments. Together, the men decided to work toward a test of engineered T cells in patients suffering from a certain family of leukemias, including chronic lymphocytic leukemia.
In 2004, June and Porter won a $1 million grant from a small foundation, the Alliance for Cancer Gene Therapy, created by two parents whose daughter-in-law had died of breast cancer. It was enough to get started. But before they could make much progress, scientific opinion shifted against them. By 2006 and 2007, teams at other universities had run their own trials of engineered T cells in cancer patients. Invariably, the cells didn’t replicate well and simply died in the blood. In one trial, they only lasted a day. The cells had no effect. They didn’t work. The whole idea was starting to seem like a bust.
This is a story about science. But science is performed by people, and people are fallible, and people are stubborn. Carl June had seen before how a field could get it wrong. Back in med school, he used to lift weights pretty seriously. Some of the guys in his gym started experimenting with anabolic steroids. June saw them suddenly zoom from benching 220 pounds to a superhuman 320. The stuff obviously worked. But when June looked up steroids in his med-school textbook, it said that they were bogus; they only appeared to work because they made your muscles retain water. It wasn’t until decades later, when juiced-up sluggers like Barry Bonds ruled the ballparks, that sc ience acknowledged steroids really could build muscle.
Even as others sprinted away from engineered T cells, June ran toward them. He couldn’t shake a sense that they were so beautiful, they had to work. The concept was sound; only the execution was lacking. It was a matter of getting the details right.
June thought he and his team at Penn could succeed where others had failed. They had a few advantages. One was a better way of growing T cells—the June/Levine system of magnetic beads, developed at the Navy. Another advantage was a custom “vector,” a sort of molecular truck for hauling new genes into a T cell. Other teams had built their trucks out of parts from viruses that cause leukemia in mice. Penn’s truck was more efficient, because its researchers had made the bold decision to build it out of HIV. HIV works by squirting its genes into T cells. Nothing on Earth is better at this task. Why not exploit it? In the lab, a researcher named Michael Milone, along with others on June’s team, had snipped away at the virus, removing the dangerous parts—the ones that let it multiply and cause AIDS—while keeping the basic chassis.
Penn had a set of unique tools, then. And the doctors used those tools to create and test various shapes of molecular limbs that no one else had tried. They injected their custom T cells into mice that had been genetically modified to accept human cells. By 2007, after testing several varieties of cells, Milone had identified one that seemed to work best, and was able to show that it could cure leukemia in mice.
Of course, scientists can cure a lot of diseases in mice that they can’t cure in people. It’s far easier and cheaper to do mouse trials than human trials. The first human-sized batch of vector—40 liters, filtered down to less than a shot glass’s worth of slightly opaque fluid for use in the trial—would cost $300,000 to make. The problem now was getting the money to scale up from mice to humans, which meant finding a funder who believed in the idea.
No one just hands money to scientists. They have to fight for it. It turned out that the main funder of cancer research in the U.S., the National Institutes of Health, didn’t want to pick up the check. Influential scientists there didn’t think engineered T cells could ever work. June reached out to a few drug companies, but they were no help, either. Big Pharma didn’t see a way to make money; the therapy was too different, too logistically demanding.
In 2008, the economy crashed, and June struggled to find money to pay his postdocs and lab assistants. He considered canceling the trial. Eventually, though, he managed to patch together funds to make the first batch of vector. It was enough for three patients.
They could feel the cancer through his skin—acorn-sized nodules of tumor in the lymph nodes under his arms. He was Bill Ludwig, a 65-year-old retired corrections officer from New Jersey. He’d come to Philly to be Patient No. 1.
At HUP, nurses hooked him up to an “apheresis” machine, which spun his blood in a centrifuge, separating his red cells and platelets from his T cells. The T cells then traveled to Levine’s Clinical Cell and Vaccine Production Facility, which was full of biosafety cabinets and scales and flasks, and refrigerators named after characters from The Simpsons: the Otto Fridge and the Maggie Fridge, along with the Krusty Freezer. Levine and his technicians added the magnetic beads and the vector to Ludwig’s T cells and put the cells in a nutrient medium that provided everything they needed to divide and grow. At this point, the mixture was the color of Earl Grey tea. The cells sat in a bag for the first few days, then were placed on a machine that rocked them gently to promote further growth. Then a magnet removed the beads, and the cells were frozen to preserve them while Levine and his team performed quality-control tests required by the FDA. After the tests were complete, the frozen bag of cells—about three ounces’ worth, or a quarter-can of soda—was taken down to Bill Ludwig’s bedside (a journey that involved rides on two elevators) and warmed in a water bath. Then a nurse hung the bag on a pole and connected it to an IV line. The fluid flowed into Ludwig.
Five days later, his temperature spiked.
David Porter studied a chest scan to try to figure out what was going on. He saw that Ludwig’s lungs looked like they had pneumonia, which is common in CLL patients. The doctors treated it with antibiotics, and it went away. But Ludwig’s fever only increased. Over the next few weeks, he grew sicker and sicker, quaking with chills, sweating with fevers. The doctors worried that maybe he was suffering from something called cytokine release syndrome, an immune system overreaction that had killed patients in other trials. Soon Porter and the other Penn doctors were dealing with end-of-life issues, like whether to put Ludwig on a respirator. Ludwig’s wife called the whole family to the hospital, fearing he would die.
In all the commotion, no one thought to look at the patient’s tumors. It wasn’t until Day 21 that an intern tried to palpate the lumps under Ludwig’s arms—and couldn’t find them.
Ludwig began to feel better. His blood counts improved; his fevers subsided. On Day 30, the team performed a battery of tests, including a CAT scan. When P orter looked at the scan, he couldn’t see any evidence of cancer. Then the team extracted some bone marrow and analyzed the cells several different ways. The first two tests showed no tumor. The third and most sensitive test showed less than one tumor cell in several hundred thousand, which more than met the definition of a complete clinical response.
Carl June thought it had to be a mistake. He asked for another bone-marrow biopsy, and for the tests to be repeated. The results of the second tests were the same: no cancer. If Ludwig still had the disease—and he might—it was beyond the current ability of medical science to detect.
The doctors obviously took this as good news, but it wasn’t as dramatic a moment for them as you might think. Medical investigators working on new kinds of treatments tend not to expect wild success. “We’ve all been involved in new approaches in treatments where the first patient, it’s miraculous, and then you treat nine people and it doesn’t work again,” Porter says. Besides, it didn’t make sense to celebrate when they didn’t yet know what was going on. All the team had was a suspicion—a rough hypothesis about what was happening inside Bill Ludwig’s body.
Sometimes when doctors give chemo drugs to patients who have never had chemo before, large quantities of tumor cells die and crack open all at once, releasing high levels of toxic junk into the blood: chemicals that mess with heart rhythms and cause other dangerous problems, as well as uric acid, which clogs the kidneys. This is called tumor lysis syndrome. Porter and June hoped that tumor lysis was the cause of Ludwig’s fevers, because if it was, it meant that the T cells were working; they were killing Ludwig’s tumors. But if it was indeed tumor lysis, it was a kind never seen before. Usually, symptoms of tumor lysis occur within a day or two of treatment. Ludwig hadn’t gotten sick until Day 5.
The Penn doctors went on to treat their second patient, who responded much as Ludwig had, with severe flu-like symptoms that swelled and ebbed; follow-up tests revealed that much, but not all, of the patient’s cancer had been eliminated. Two successes were better than one, but two could still be a fluke; two could be an accident. It wasn’t until the doctors treated Patient No. 3, a 64-year-old Bucks County man named Douglas Olson, that they got a clear picture of what they were achieving.
Olson, a scientist himself and a longtime patient of Porter’s, had come into the trial with three pounds of tumors in his body. The tumors had proven resistant to all other therapies, and he didn’t want to try a bone-marrow transplant. “If you survive it,” Olson says, “you may not be cured, and you can’t do it again. So this trial was a chance to beat this thing.”
Something was different about Olson, something that made him a particularly useful test case: His T cells hadn’t grown well in the lab. The team could only give him one one-hundredth of the dose of T cells given to the first patient. It was such a low dose that some colleagues at Penn didn’t think it was ethical to treat the patient at all. Says Porter, “There were people who were going to insist he sign a consent that he knows this is futile. And we just argued, ‘We don’t know that.’”
The team won the argument and went ahead with the infusion. Fourteen days later, Olson woke up with fevers and chills. He called Porter, who told him to come in for some tests. “Now I had a sense of what was going on,” Porter says. “That this was, in fact, good news.”
Over the next week, Olson felt nauseated and suffered from diarrhea; he couldn’t eat. (As the doctors would later discover, what was making the patients feel like they had the worst flu of their lives was cytokine release syndrome.) On the evening of Day 21, Porter was walking across the Penn campus when he got a text message on his pager. It was a series of lab results on Olson.
June got the results the next morning in his office. He scanned through columns of numbers, mouth agape. One of his colleagues, Michael Kalos, had spent years designing a series of ultra-precise assays to measure the activity of T cells in the blood, and now Kalos’s assays were telling an incredible story. On Day Five, there had been almost no engineered T cells in the patient’s body. By Day 18, there were billions. They had multiplied a thousand-fold from the original tiny dose. Almost every T cell in the patient’s body was one of Penn’s special genetic creatures. The patient was growing the drug in his body.
What’s more, the lab results painted a picture of cataclysm in Olson’s blood. As the T cells grew exponentially, the patient’s kidneys had begun to shut down, and all sorts of chemicals associated with tumor lysis syndrome were wreaking havoc. It was really happening, all of it—cell growth, tumor death—exactly as the team had intended.
Two days later, Olson’s bone-marrow biopsy came back clean. Three days after that, doctors discharged him from the hospital, an apparently healthy man. “I was absolutely cancer-free,” Olson says. “I gotta tell you, every time I say that, it just gives me the shivers.” The day he left the hospital, Olson drove to Maryland with his wife, to the Annapolis Boat Show, and bought an 18-foot sailboat.
The temptation was to say that pounds of tumors had “melted away,” but melting implied a gentle process, and what had happened to the tumors was more violent than that. They’d been either torn to shreds directly by T cells that acted like serial killers, moving from one tumor cell to the next, slashing membranes and spilling innards, or they’d been destroyed by enzymes secreted by the T cells.
In follow-up tests six months later, the team would find high levels of engineered T cells still alive in Olson’s blood. And no detectable tumors.
It was ingrained in them, through their training, to resist celebration. After June and his colleagues got the initial results for Olson, they thought about all the things they still didn’t know. Why, exactly, had the therapy worked so well? Was it the particular structure of the engineered cells? Was it the way they’d grown the cells, using the body as a sort of bioreactor? Was cancer still lurking below the threshold of detection?
They knew it would take years to answer these questions. They also knew that “something unprecedented had happened,” June says. The responsible thing to do with such data is to publish it and let other scientists take a look, and that’s exactly what the Penn doctors did. They submitted papers to two prestigious journals, the New England Journal of Medicine and Science Translational Medicine, and as the papers circulated, scientists quickly recognized their significance—especially the handful of researchers who, like June, had always believed that this approach could work. “The Penn trial was definitely a turning point,” says Michel Sadelain, a researcher at Memorial Sloan-Kettering Cancer Center who has made important contributions to the study of engineered T cells. “In the first three patients Carl treated, two of them showed a very dramatic response. It couldn’t be any more dramatic. They had large tumor burdens that essentially vanished.” Laurence Cooper at MD Anderson describes the transformation of the initial patients as “a sort of Lazarus moment.”
Lazarus moment or no, there were still scientists who didn’t buy that Penn was onto something big. The argument for skepticism rested less on science than logistics. Penn was a small operation—a boutique. Sure, they could treat three patients, but what about 300, or 3,000? Penn hadn’t shown it could even begin to meet the need. Maybe the therapy was inherently impractical.
No one was more painfully aware of Penn’s limitations than David Porter. In late 2011 and early 2012, after news of the breakthrough spread from the scientific literature into media around the world, more than 5,000 emails flooded into Penn, begging for access to the trial. “She is our first-born and only girl,” went a typical letter from a mother and father hoping to get treatment for their daughter with leukemia. “We both love her very very much.”
Porter read these letters with anguish. He knew Penn only had the capacity to treat seven or eight more people over the next year. Besides, the therapy was still so new. He didn’t know all the side effects yet. It wouldn’t be responsible to throw the trial open to more than a few.
How do you explain the need for scientific caution to the parent of a dying child?
Here is what Porter ended up telling people: “We’re doing this as fast as we can.”
Walt got into the trial because his family fought for him. It’s really that simple.
Penn had set up an online application for the trial. Walt wasn’t good with computers, so his eldest sister, Nancy Nelson, a woman in her early 60s with dirty-blond hair and glasses, filled out the form and hit SEND.
Nancy and Walt had always been extremely close; they’d bonded as kids in Montclair, relying on each other to process the trauma of their mother’s murder. Nancy had already decided that if Walt got into the trial, she would leave California to be at his side for however long it took. Walt’s wife, Robin, couldn’t do it. Their relationship had lately become rocky; besides, she had to stay at her job to keep Walt’s health insurance current.
Nancy received a brief email response from Penn—a form letter. Then, nothing. “We figured out pretty quickly that it was just going into a black hole,” she recalls.
Eventually, after two weeks of calls and prayers, Walt’s daughter Chelle connected with a researcher who worked for David Porter. They spoke for half an hour. “He explained to me that it was very high-risk,” Chelle remembers. “That my father could die. The new cells could eat up his whole body.” She asked the researcher a question: If it were his father, what would he do? According to Chelle, the man said, “Oooooh. I don’t know.”
Chelle didn’t hesitate: Her father had made his wishes clear. She set up an appointment for Walt to meet Porter.
Walt and Nancy flew to Philadelphia for the meeting in November 2011. “If you let me into the trial,” Walt told Porter, “I promise I’ll be the best patient you’ve ever had. I promise I’ll make it.” Porter took this as a good sign; an early-stage medical trial demands “some incredible amount of optimism” on the part of the patient. It also boded well that Nancy was here, wearing a silver necklace that said CURE WALT. Porter didn’t commit, though. He told them how difficult the journey would be. A bone-marrow transplant was the tried-and-true option.
Walt said no. He wanted this.
Porter agreed to run blood tests to see if Walt’s cells would respond to the vector. In March 2012, Walt got the call: He was in.
The next few months were among the most agonizing of his life. His health began to fluctuate, because his leukemia was progressing. Doctors at Penn requested extra tests. Next, Penn ran out of vector—they’d used up their first two batches on the first six patients—and he had to wait for a new batch to be ready. He had to cool his heels. By now, he and Nancy had left California and come to the Philly area in anticipation of Walt’s infusion. They were staying in Cheltenham, in a free hotel for cancer patients and their caregivers called Hope Lodge, run by the drug company AstraZeneca. They ate their meals in a communal dining room, chatting with the other patients about the Phillies.
Then, in April 2012, Penn suddenly suspended the trial. They’d begun treating their first child patient, Emma Whitehead, a six-year-old girl who suffered from acute lymphoblastic leukemia, a disease similar to CLL. After Emma received her dose of T cells, her body’s immune system had revved up, releasing cytokines that caused fever, nausea, hypoxia (low oxygen) and low blood pressure. Doctors decided to administer an anti-cytokine agent called tocilizumab. They paused the trial to make sure she’d be okay.
When Emma recovered, the trial resumed. Walt finally received his infusion of T cells on Tuesday, May 15th. Chelle couldn’t be there, so she texted Nancy a prayer to read out loud:
Father God, we ask for your blessing on these cells. Let this blessing flow right from you to Walt. May these cells be of You, Lord. May they heal, restore and give life. …
The first night, Walt spiked a fever.
This was unexpected. Previous patients had taken five to 14 days to get sick. The doctors tested Walt’s blood. What they found surprised them: By Day 3, Walt had higher than expected levels of engineered T cells in his blood. His bioreactor was churning with astonishing speed.
Walt started feeling better over the next few days. He even penned some coaching advice for his players in an online journal Nancy had been maintaining:
Wyatt, remember to pick up the target early and on your fastball make sure to keep your hand behind the ball.
Alec, don’t worry about your speed. Your strength is hitting your spots and changing speed of pitches.…
On the morning of the sixth day after infusion, Nancy woke up in Hope Lodge and checked on Walt. Walt wouldn’t get out of bed. He seemed more tired than ever. Nancy couldn’t get him to eat or to drink much water. She called Porter, who said to bring him to the hospital right away. When they arrived, a nurse tried to get blood from Walt but couldn’t find a vein. His blood pressure had crashed. Doctors rolled him into the emergency room.
From here on in, Walt’s memories are fuzzy. He has a particular way of characterizing this lost time: “I fell into the ditch.”
His kids came to Philly when they heard he was worsening. Chelle arrived on the night of Wednesday, May 23rd; Shawna and Dustin came the next day on a red-eye flight, sprinting from the airport to a cab and from the cab to the hospital. “I thought I was coming to say goodbye,” says Shawna, a 38-year-old with curly hair who works in an orthodontist office in California. When she finally got to Walt’s room, she had to step back and take a minute to compose herself. It was mostly his eyes: They looked like they were bleeding.
The kids slept fitfully in chairs next to their father’s bed. They chatted with the nurses caring for Walt and looked forward to the twice-daily visits from Dr. Porter, whose archetypically calm bedside manner helped reassure them that Walt would be okay. Porter had seen many of Walt’s symptoms crop up in previous patients, and by now he had a better sense of how to deal with them. He knew he could tamp down the activity of the T cells by administering tocilizumab, the anti-cytokine agent. What he didn’t know was this: By suppressing the T cells, would he also prevent them from killing Walt’s tumors?
When Porter asked Walt if he wanted the anti-cytokine agent, Walt shook his head vigorously: He didn’t want to risk stopping the beneficial part of the reaction.
Let these puppies work, Walt thought.
By Friday night, though, 10 days after infusion, Walt was no longer able to make decisions for himself. He started babbling to his sister and his children about Elvis Presley. He told them he had to get out of his bed.
Porter talked to Chelle and Nancy, and they all agreed that even though it might reduce the efficacy of the T cells, they shouldn’t wait any longer to administer the agent. The staff gave it to Walt, then moved him into the intensive-care unit.
The scariest moment for Walt’s family came a short time later, around 10 on Saturday night, when Walt started to repeat the same phrase over and over. “I need to go,” he said, a faraway look in his eyes. “I need to go. I see the white wedding.” To Dustin, it was like something out of a movie: His father was telling him that he could see the light, that he was sick of fighting and he wanted to die.
Chelle said, “That’s okay, Dad. You can go.” She’d miss him if he died, of course, but the way Chelle saw it, God was in control, not the family. If God wanted to take Walt, that was His will.
“No!” Shawna screamed.
Dustin began to cry. “No, Dad, don’t go.”
Dustin held his father’s hand. Walt gripped back, tightly. Then he let go.
This is it, Dustin thought.
But then Walt opened his eyes.
He did that a few more times, gripping and letting go, gripping and letting go. Finally, he slept.
The next morning, when Walt woke up, his family thought he looked better. It seemed like he had regained his voice and some of his vigor. The anti-cytokine agent was working. Over the next few days, Walt’s physical state continued to improve. His thinking was still muddled, though, which meant that things got harder for the family, not easier, because now Walt could actually pull himself up onto the rails of his bed in an attempt to escape. Nancy and the kids took turns playing prison guard. They would lie on top of him, hug him close, just to keep him down. There was a rope above Walt’s bed attached to a hook that the nurses could use to hoist him up. At one point, Walt grabbed onto the rope with both hands like it was a water-ski line and said to the nurses, “Hit it,” which is the signal a water-skier gives to the speedboat driver to start the engines.
Then, over the next several days, Walt was moved to a regular hospital room and started to climb out of the ditch. Nancy had taken to playing Motown music on her iPad. One day she noticed Walt humming along to “You’ve Really Got a Hold on Me”:
I don’t like you, but I love you. …
Don’t wanna kiss you, but I need to.
Another time, Walt elevated himself on the side of the bed and started jiggling. A nurse asked him what he was doing. “Shaking my booty,” Walt said, and sang: Shake shake shake, shake shake shake your booo-tay.
The day they really knew Walt was back, though, was the day Dr. Porter walked into the room to ask the four questions—
What’s your full name?
Where are you?
What month is it?
What day of the week is it?
—and Walt answered them before Porter could even speak: “I’m Walter Robert Keller, I’m at the Hospital of the University of Pennsylvania, it’s May, and today’s Thursday.”
“That was awesome, Walt,” Porter said.
Soon Walt got out of bed, moseying through the hallways with a walker. Around that time, on June 5th, Porter took a sample of Walt’s bone marrow to check on the status of his cancer. The lab report came back six days later, on June 11th. Accompanied by several staffers, Porter came to Walt’s room to give him and Nancy the news.
The doctors clustered around Walt. “All of us were trying not to jump up and down,” Porter recalls.
Before the trial, 90 percent of Walt’s bone marrow cells had been cancerous. Now, doctors couldn’t find any trace of the disease, Porter said. They still had to do more tests. But Walt appeared to be in complete remission. Up to seven pounds of tumor, obliterated, gone.
“His eyes were, like, lit up,” Walt recalls of Porter. “When someone tells you you have cancer, and then when someone tells you you don’t have any—oh, it was like a monkey just jumped off my back.”
Walt stayed in the hospital for a few more days, working with a physical therapist to regain strength in his atrophied muscles. He and Nancy moved back to Hope Lodge for a time, then returned home to California in July.
Meanwhile, in Philly, the Penn team went on to treat adult patients No. 8, 9 and 10, as well as a second child, for a total of 12. (One of the patients in the second trio—4, 5 and 6—had a partial response to the therapy, while two others saw no effect on their cancer; another adult among the first 12 patients also did not respond.)
Last December, at a medical conference in Atlanta, the team presented its results to a rapt audience. The data boiled down to this: Nine out of the 12 patients, including both of the children, had responded to the therapy. Nine out of 12 had grown the engineered T cells in their bodies. Nine out of 12 had experienced some degree of tumor lysis syndrome and had seen their tumors vanish, either partially or completely.
Even more encouraging were the follow-up data on the two early cases of compete remission—patients No. 1, Bill Ludwig, and No. 3, Douglas Olson.
One big question all along has been the durability of the T cells. How long will they stay alive in the blood? Months? Years? Will cancer return in these patients? Doctors don’t know. “I don’t think we’ve proven that we’ve cured anyone,” Porter says. Still, when Ludwig and Olson returned to Philly for their two-year checkups in the fall of 2012, they told doctors they felt great. The team checked their blood. The T cells were still alive, two years after infusion. Cancer undetectable.
“I think of these guys as the first astronauts, right?” says Levine. “They didn’t know what they were getting into. They signed up for something, and it’s wonderful to see how it’s turned out.”
“I mean, I thought it might work,” June says, “but I didn’t think it would work as well as it did.”
Science is incremental. It’s a slow and global grind, a steady accumulation of facts wrested from failure. But every once in a while, there really is a leap, and a small group of people can change how thousands think about the possibilities.
Carl June argued for years that engineered T cells could work, without much to show for it. But thanks to the trial, people are starting to listen. Even Big Pharma wants in.
For months, Penn has been working with the Swiss pharmaceutical giant Novartis, which manufactures the cancer drug Gleevec and the ADHD drug Ritalin, among others. According to the terms of a deal struck last year, Novartis will soon construct a new building on the Penn campus, the Center for Advanced Cellular Therapies, where Penn researchers will partner with scientists from Novartis to develop the T-cell technology.
Pharmaceutical companies have collaborated with universities before, but never to address the unique challenges that lie ahead for this particular drug. Novartis will help Penn learn more about the inner workings of the therapy so they can better channel and control it, hopefully sparing future patients ordeals like Walt’s. It will pay for the costly Phase 2 and Phase 3 trials required to win FDA approval. It will help test the technology in other kinds of cancers: June and his team now have trials in the planning stages for mesothelioma (a lung-lining cancer); pancreatic, brain, prostate, breast and ovarian cancers; and other blood cancers. And for the first time, a pharmaceutical company will design a manufacturing system that takes blood from the patient, modifies it in the lab, and gives it back to the patient. The biggest challenge here isn’t proving that the drug works; the biggest challenge is making it.
These days, Carl June spends a lot of time thinking about biology on an industrial scale—the unsexy details of cell cultures and workflows in the factory he wants to build. But when he’s not thinking about the very large, he marvels at the very small. At the power of the Penn trial, given its size. A few well-described cases “can really change the whole field,” he says. A couple of brave men. Two kids. That’s all. And look.
2012, West Covina, California
“Nice and easy, okay?” Walt tells the starting pitcher of his Upland Underdogs, a 13-year-old named J.J. with orange sunglasses. It’s a bright October Sunday, and Walt is in the bullpen with J.J. before a game. “You struck out nine guys on this team last time,” Walt says. “Okay, remember, you’re like a tree falling in the forest, okay? Don’t overthrow.” A spindly arm wheels around, and the ball smacks into the catcher’s glove. “Good, J.J.”
The opponents, West Covina, are batting first. Walt jogs out onto the field and takes up his position as first-base coach. He can jog now. He can stand in the sun and shout at the kids in the dugout to stop goofing around and pay attention to the pitcher’s moves.
It’s been three months since Walt came home from Philadelphia. His kidneys aren’t quite back to 100 percent. When he goes out in public, he sometimes wears one of his painting masks to protect his immune system, and from time to time his feet go numb and he has trouble pressing the gas pedal on his truck. Yet he can feel his body coming back. There are days when he wakes up clear-headed, when he’s full of weird energy and he wanders around confused until it suddenly occurs to him: This is what it feels like to be healthy. A year ago, Walt had given up planning for a future he didn’t think would ever come, but now he’s thinking about expanding his wood-fin ishing bu siness. He’s even started to wonder, half seriously, about scoring his ultimate dream job: pitching coach for a minor—and eventually major—league baseball team. Decades of coaching experience under his belt—why not?
Walt’s kids are here today, Dustin and Shawna and Chelle, watching in the stands, telling stories about the trial.
“It’s an indescribable feeling, finding out his bone marrow is clean,” Dustin says, gazing out at the diamond. “It’s surreal. It’s still surreal. I’m in disbelief.”
West Covina cycles through three pitchers in four innings. The game finally tips in the fifth, when Walt’s team explodes for 15 runs. The rally-capper is a home run that sails well over the second fence in center field.
Final score: 22-5, Upland. A football score. Walt shakes his head. He tucks his chin into his neck and smiles. Then he jogs across the diamond with the kids to shake hands with the vanquished.