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Patient No. 7machine that rocked them gently to promotefurther growth. Then a magnet removed thebeads, and the cells were frozen to preservethem while Levine and his team performedquality-control tests required by the FDA.After the tests were complete, the frozenbag of cells—about three ounces’ worth, or aquarter-can of soda—was taken down to BillLudwig’s bedside (a journey that involvedrides on two elevators) and warmed in awater bath. Then a nurse hung the bag on apole and connected it to an IV line. The fluidflowed into Ludwig.Five days later, his temperature spiked.David Porter studied a chest scan totry to figure out what was going on. Hesaw that Ludwig’s lungs looked like theyhad pneumonia, which is common in CLLpatients. The doctors treated it with antibiotics,and it went away. But Ludwig’sfever only increased. Over the next fewweeks, he grew sicker and sicker, quakingwith chills, sweating with fevers.The doctors worried that maybe he wassuffering from something called cytokinerelease syndrome, an immunesystem overreaction that had killed patientsin other trials. Soon Porter and the otherPenn doctors were dealing with end-oflifeissues, like whether to put Ludwig on arespirator. Ludwig’s wife called the wholefamily to the hospital, fearing he would die.In all the commotion, no one thought tolook at the patient’s tumors. It wasn’t untilDay 21 that an intern tried to palpate thelumps under Ludwig’s arms—and couldn’tfi n dt h e m .Ludwig began to feel better. His bloodcounts improved; his fevers subsided. OnDay 30, the team performed a battery oftests, including a CAT scan. When P orterlooked at the scan, he couldn’t see any evidenceof cancer. Then the team extractedsome bone marrow and analyzed the cellsseveral different ways. The first two testsshowed no tumor. The third and mostse nsitive test showed less than one tumorcell in several hundred thousand, whichmore than met the definition of a completeclinical 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 ofthe second tests were the same: no cancer. IfLudwig still had the disease—and he might—it was beyond the current ability of medicalscience to detect.The T cells hadmultiplied athousand-fold. Thepatient was growingthe drug in his body.The doctors obviously took this as goodnews, but it wasn’t as dramatic a moment forthem as you might think. Medical investigatorsworking on new kinds of treatmentstend not to expect wild success. “We’ve allbeen involved in new approaches in treatmentswhere the first patient, it’s miraculous,and then you treat nine people and itdoesn’t work again,” Porter says. Besides, itdidn’t make sense to celebrate when theydidn’t yet know what was going on. All theteam had was a suspicion—a rough hypothesisabout what was happening inside BillLudwig’s body.Sometimes when doctors give chemodrugs to patients who have never had chemobefore, large quantities of tumor cells die andcrack open all at once, releasing high levels oftoxic junk into the blood: chemicals that messwith heart rhythms and cause other dangerousproblems, as well as uric acid, which clogsthe kidneys. This is called tumor lysis syndrome.Porter and June hoped that tumor lysiswas the cause of Ludwig’s fevers, because if itwas, it meant that the T cells were working;they were killing Ludwig’s tumors. But if itwas indeed tumor lysis, it was a kind neverseen before. Usually, symptoms of tumor lysisoccur within a day or two of treatment. Ludwighadn’t gotten sick until Day 5.The Penn doctors went on to treat theirsecond patient, who responded much asLudwig had, with severe flu-like symptomsthat swelled and ebbed; follow-uptests revealed that much, but not all, ofthe patient’s cancer had been eliminated.Two successes were better than one, buttwo could still be a fluke; two could be anaccident. It wasn’t until the doctors treatedPatient No. 3, a 64-year-old Bucks Countyman named Douglas Olson, that they got aclear picture of what they were achieving.Olson, a scientist himself and a longtimepatient of Porter’s, had come into the trialwith three pounds of tumors in his body.The tumors had proven resistant to all othertherapies, and he didn’t want to try a bonemarrowtransplant. “If you survive it,” Olsonsays, “you may not be cured, and you can’tdo it again. So this trial was a chance to beatthis thing.”Something was different about Olson,something that made him a particularly usefultest case: His T cells hadn’t grown well inthe lab. The team could only give him oneone-hundredth of the dose of T cells given tothe first patient. It was such a low dose thatsome colleagues at Penn didn’t think it wasethical to treat the patient at all. Says Porter,“There were people who were going to insisthe sign a consent that he knows this is futile.And we just argued, ‘We don’t know that.’”The team won the argument and wentahead with the infusion. Fourteen dayslater, Olson woke up with fevers and chills.He called Porter, who told him to come infor some tests. “Now I had a sense of whatwas going on,” Porter says. “That this was,in fact, good news.”Over the next week, Olson felt nauseatedand suffered from diarrhea; he couldn’t eat.(As the doctors would later discover, whatwas making the patients feel like they hadthe worst flu of their lives was cytokinerelease syndrome.) On the evening of Day 21,Porter was walking across the Penn campuswhen he got a text message on his pager. Itwas a series of lab results on Olson.June got the results the next morning inhis office. He scanned through columns ofnumbers, mouth agape. One of his colleagues,Michael Kalos, had spent years designing aseries of ultra-precise assays to measurethe activity of T cells in the blood, and nowKalos’s assays were telling an incredible story.On Day Five, there had been almost no engineeredT cells in the patient’s body. By Day18, there were billions. They had multiplieda thousand-fold from the original tiny dose.Almost every T cell in the patient’s body wasone of Penn’s special genetic creatures. Th epatient was growing the drug in his body.What’s more, the lab results painted apicture of cataclysm in Olson’s blood. As theT cells grew exponentially, the patient’s kidneyshad begun to shut down, and all sorts ofchemicals associated with tumor lysis syndromewere wreaking havoc. It was reallyhappening, all of it—cell growth, tumordeath—exactly as the team had intended.Two days later, Olson’s bone-marrowbiopsy came back clean. Three days afterthat, doctors discharged him from the hos-pital, an apparently healthy man. “I wasabsolutely cancer-free,” Olson says. “I gottatell you, every time I say that, it just givesme the shivers.” The day he left the hospital,Olson drove to Maryland with his wife,to the Annapolis Boat Show, and bought an18-foot sailboat.The temptation was to say that poundsof tumors had “melted away,” but meltingimplied a gentle process, and what hadhappened to the tumors was more violentthan that. They’d been either torn to shredsdirectly by T cells that acted like serial killers,moving from one tumor cell to the next,slashing membranes and spilling innards, orthey’d been destroyed by enzymes secretedby the T cells.In follow-up tests six months later, theteam would find high levels of engineeredT cells still alive in Olson’s blood. And nodetectable tumors.IT WAS INGRAINED in them, through theirtraining, to resist celebration. After Juneand his colleagues got the initial results forOlson, they thought about all the things theystill didn’t know. Why, exactly, had the therapyworked so well? Was it the particularstructure of the engineered cells? Was it theway they’d grown the cells, using the body asa sort of bioreactor? Was cancer still lurkingbelow the threshold of detection?They knew it would take years to answerthese questions. They also knew that “somethingunprecedented had happened,” Junesays. The responsible thing to do with suchdata is to publish it and let other scientiststake a look, and that’s exactly what the Penndoctors did. They submitted papers to twoprestigious journals, the New England Journalof Medicine and Science Translational Medicine,and as the papers circulated, scientistsquickly recognized their sig nificance—e specially the handful of researchers who,like June, had always believed that thisapproach could work. “The Penn trial wasdefinitely a turning point,” says MichelS adelain, a researcher at Memorial Sloan-Kettering Cancer Center who has madeimportant contributions to the study of engineeredT cells. “In the first three patients Carltreated, two of them showed a very dramaticresponse. It couldn’t be any more dramatic.They had large tumor burdens that essentiallyvanished.” Laurence Cooper at MD Andersondescribes the transformation of the initialpatients as “a sort of Lazarus moment.”198 philadelphia august 2013 august 2013 philadelphia 199

Patient No. 7sion of T cells on Tuesday, May 15th. Chellecouldn’t be there, so she texted Nancy aprayer to read out loud:Father God, we ask for your blessing on thesecells. Let this blessing flow right from you toWalt. May these cells be of You, Lord. May theyheal, restore and give life. …THE FIRST NIGHT, Walt spiked a fever.This was unexpected. Previous patientshad taken five to 14 days to get sick. The doctorstested Walt’s blood. What they foundsurprised them: By Day 3, Walt had higherthan expected levels of engineered T cells inhis blood. His bioreactor was churning withastonishing speed.Walt started feeling better over the nextfew days. He even penned some coachingadvice for his players in an online journalNancy had been maintaining:Wyatt, remember to pick up the target earlyand on your fastball make sure to keep yourhand behind the ball.Alec, don’t worry about your speed. Yourstrength is hitting your spots and changingspeed of pitches.…On the morning of the sixth day afterinfusion, Nancy woke up in Hope Lodge andchecked on Walt. Walt wouldn’t get out ofbed. He seemed more tired than ever. Nancycouldn’t get him to eat or to drink muchwater. She called Porter, who said to bringhim to the hospital right away. When theyarrived, a nurse tried to get blood from Waltbut couldn’t find a vein. His blood pressurehad crashed. Doctors rolled him into theemergency room.From here on in, Walt’s memories arefuzzy. He has a particular way of characterizingthis lost time: “I fell into the ditch.”His kids came to Philly when they heardhe was worsening. Chelle arrived on thenight of Wednesday, May 23rd; Shawnaand Dustin came the next day on a red-eyeflight, sprinting from the airport to a caband from the cab to the hospital. “I thoughtI was coming to say goodbye,” says Shawna,a 38-year-old with curly hair who works inan orthodontist office in California. Whenshe finally got to Walt’s room, she had tostep back and take a minute to composeherself. It was mostly his eyes: They lookedlike they were bleeding.The kids slept fitfully in chairs next totheir father’s bed. They chatted with thenurses caring for Walt and looked forward tothe twice-daily visits from Dr. Porter, whosearchetypically calm bedside manner helpedreassure them that Walt would be okay. Porterhad seen many of Walt’s symptoms cropup in previous patients, and by now he hada better sense of how to deal with them. Heknew he could tamp down the activity ofthe T cells by administering tocilizumab,the anti-cytokine agent. What he didn’tknow was this: By suppressing the T cells,would he also prevent them from killingWalt’s tumors?When Porter asked Walt if he wanted theanti-cytokine agent, Walt shook his headvigorously: He didn’t want to risk stoppingthe beneficial part of the reaction.Let these puppies work, Walt thought.BY FRIDAY NIGHT, though, 10 days afterinfusion, Walt was no longer able to makedecisions for himself. He started babbling tohis sister and his children about Elvis Presley.He told them he had to get out of his bed.Porter talked to Chelle and Nancy, andthey all agreed that even though it mightreduce the efficacy of the T cells, theyshouldn’t wait any longer to administer theagent. The staff gave it to Walt, then movedhim into the intensive-care unit.The scariest moment for Walt’s familycame a short time later, around 10 on Saturdaynight, when Walt started to repeat thesame phrase over and over. “I need to go,” hesaid, a faraway look in his eyes. “I need togo. I see the white wedding.” To Dustin, it waslike something out of a movie: His father wastelling him that he could see the light, thathe was sick of fighting and he wanted to die.Chelle said, “That’s okay, Dad. You cango.” She’d miss him if he died, of course, butthe 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. Waltgripped back, tightly. Then he let go.This is it, Dustin thought.But then Walt opened his eyes.He did that a few more times, grippingand letting go, gripping and letting go. Finally,he slept.The next morning, when Walt wokeup, his family thought he looked better. Itseemed like he had regained his voice andsome of his vigor. The anti-cytokine agentwas working. Over the next few days, Walt’sphysical state continued to improve. Histhinking was still muddled, though, whichmeant that things got harder for the family,not easier, because now Walt could actuallypull himself up onto the rails of his bed in anattempt to escape. Nancy and the kids tookturns playing prison guard. They would lieon top of him, hug him close, just to keep himdown. There was a rope above Walt’s bedattached to a hook that the nurses could useto hoist him up. At one point, Walt grabbedonto the rope with both hands like it was awater-ski line and said to the nurses, “Hitit,” which is the signal a water-skier givesto the speedboat driver to start the engines.Then, over the next several days, Waltwas moved to a regular hospital room andstarted to climb out of the ditch. Nancy hadtaken 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 onthe side of the bed and started jiggling. Anurse asked him what he was doing. “Shakingmy booty,” Walt said, and sang: Shakeshake shake, shake shake shake your booo-tay.The day they really knew Walt was back,though, was the day Dr. Porter walked intothe 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 Portercould 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, moseyingthrough the hallways with a walker. Aroundthat time, on June 5th, Porter took a sampleof Walt’s bone marrow to check on the statusof his cancer. The lab report came backsix days later, on June 11th. Accompanied byseveral staffers, Porter came to Walt’s roomto give him and Nancy the news.The doctors clustered around Walt. “Allof us were trying not to jump up and down,”202 philadelphia august 2013

Patient No. 7Porter recalls.Before the trial, 90 percent of Walt’s bonemarrow cells had been cancerous. Now, doctorscouldn’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 recallsof Porter. “When someone tells you you havecancer, and then when someone tells youyou don’t have any—oh, it was like a monkeyjust jumped off my back.”WALT STAYED IN the hospital for a fewmore days, working with a physical therapistto regain strength in his atrophiedmuscles. He and Nancy moved back to HopeLodge for a time, then returned home toCalifornia in July.Meanwhile, in Philly, the Penn teamwent on to treat adult patients No. 8, 9 and10, as well as a second child, for a total of 12.(One of the patients in the second trio—4, 5and 6—had a partial response to the therapy,while two others saw no effect on theircancer; another adult among the first 12patients also did not respond.)Last December, at a medical conferencein Atlanta, the team presented its results toa rapt audience. The data boiled down tothis: Nine out of the 12 patients, includingboth of the children, had responded to thetherapy. Nine out of 12 had grown the engineeredT cells in their bodies. Nine out of 12had experienced some degree of tumor lysissyndrome and had seen their tumors vanish,either partially or completely.Even more encouraging were the followupdata on the two early cases of competeremission—patients No. 1, Bill Ludwig, andNo. 3, Douglas Olson.One big question all along has been thedurability of the T cells. How long will theystay alive in the blood? Months? Years? Willcancer return in these patients? Doctorsdon’t know. “I don’t think we’ve proven thatwe’ve cured anyone,” Porter says. Still, whenLudwig and Olson returned to Philly for theirtwo-year checkups in the fall of 2012, theytold doctors they felt great. The team checkedtheir blood. The T cells were still alive, twoyears after infusion. Cancer undetectable.“I think of these guys as the first astronauts,right?” says Levine. “They didn’tknow what they were getting into. Theysigned up for something, and it’s wonder-ful to see how it’s turned out.”“I mean, I thought it might work,” Junesays, “but I didn’t think it would work aswell as it did.”SCIENCE IS INCREMENTAL. It’s a slow andglobal grind, a steady accumulation of factswrested from failure. But every once ina while, there really is a leap, and a smallgroup of people can change how thousandsthink about the possibilities.Carl June argued for years that engineeredT cells could work, without much toshow for it. But thanks to the trial, people arestarting to listen. Even Big Pharma wants in.For months, Penn has been working withthe Swiss pharmaceutical giant Novartis,which manufactures the cancer drug Gleevecand the ADHD drug Ritalin, among others.According to the terms of a deal struck lastyear, Novartis will soon construct a newbuilding on the Penn campus, the Center forAdvanced Cellular Therapies, where Pennresearchers will partner with scientists fromNovartis to develop the T-cell technology.Pharmaceutical companies have collaboratedwith universities before, but never toaddress the unique challenges that lie aheadfor this particular drug. Novartis will helpPenn learn more about the inner workings ofthe therapy so they can better channel andcontrol it, hopefully sparing future patientsordeals like Walt’s. It will pay for the costlyPhase 2 and Phase 3 trials required to winFDA approval. It will help test the technologyin other kinds of cancers: June and histeam now have trials in the planning stagesfor mesothelioma (a lung-lining cancer);pancreatic, brain, prostate, breast and ovariancancers; and other blood cancers. Andfor the first time, a pharmaceutical companywill design a manufacturing systemthat takes blood from the patient, modifiesit in the lab, and gives it back to the patient.The biggest challenge here isn’t provingthat the drug works; the biggest challengeis making it.These days, Carl June spends a lot of timethinking about biology on an industrialscale—the unsexy details of cell cultures andworkflows in the factory he wants to build.But when he’s not thinking about the verylarge, he marvels at the very small. At thepower of the Penn trial, given its size. A fewwell-described cases “can really change thewhole field,” he says. A couple of brave men.Two kids. That’s all. And look.august 2013 philadelphia 205

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