Has Carl June Found a Key to Fighting Cancer? - - Philadelphia Magazine (PA) - August 1, 2013
`August 1,2013 | Philadelphia Magazine (PA) | Jason Fagone
`
`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?
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`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
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`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
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`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
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`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
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`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
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`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 knowjesus.
`"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.
`
`2004, Philadelphia
`
`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
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`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. Butjune 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
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`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
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`to make the first batch of vector. It was enough for three patients.
`
`2010, Philadelphia
`
`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 Newjersey. 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
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`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
`
`UPenn Ex. 2001
`Miltenyi v. UPenn
`IPR2022-00855
`Page 11
`
`

`

`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, everytime I say that, it just gives me the shivers." The day he left the hospital,
`Olson drove to Maryland with his wif