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`The Dizzying Journey
`To a New Cancer Arsenal
`
`Carl June and others are on a quest to make T cell therapy a cancer treatment
`success. Getting there is fi lled with highs and lows and lots of uncertainty
`
`CREDIT: ERIC MENCHER/PENN MEDICINE
`
`in Olson and one other patient. The third man
`responded partly but later died of his disease.
`Funders deemed the therapy too experimen-
`tal and too impractical. Everywhere, Porter
`and June were turned down.
`“It was one of these best of all times, worst
`of all times,” says June, who had assembled
`his small team, including Porter, more than
`a decade ago. They weren’t the fi rst to test
`this radical new approach in people, but their
`results were the most striking. “We knew
`something worked,” even if the remissions
`ended tomorrow, June says. “We knew it
`wasn’t an accident.”
`Sipping coffee, Porter and June weighed
`their next step. They were itching to test the
`cell therapy in more people with leukemia,
`and to do that they needed money that they
`
`strategy had worked beyond the doctors’ wild-
`est expectations, melting away pounds of
`tumor in each patient. In one case, the modi-
`fi ed cells didn’t grow well in the lab, and the
`patient, a 64-year-old scientist at a biotech-
`nology company named Douglas Olson,
`received a mouse-sized dose. Now, he’d taken
`up running as a hobby and was teaching his
`grandchildren how to sail.
`But generating the cells for all three
`patients had cost $350,000. The scientists
`were out of money and out of “vector,” the
`disabled HIV viruses that they were using
`to insert new genes into T cells. They had
`applied to the National Cancer Institute
`(NCI) and elsewhere for funding to continue
`their clinical trial, sharing unpublished data
`on patients 1, 2, and 3. Cancer had vanished
`
`ONE JANUARY AFTERNOON IN 2011,
`oncologists Carl June and David Porter settled
`themselves at a table at Gia Pronto, the cof-
`fee shop in the atrium of the Perelman Center
`for Advanced Medicine. The glass and steel
`building sits at the nerve center of the Uni-
`versity of Pennsylvania’s (Penn’s) massive
`medical complex in West Philadelphia, a few
`blocks from the Schuylkill River that cuts the
`city in two. Outside, construction cranes rise
`up, a sign of Penn’s ongoing expansion.
`June and Porter had a problem. In an exhil-
`arating 6 weeks in the summer of 2010, they
`had treated three men with leukemia who
`were out of options. In a cell therapy experi-
`ment, the patients’ own T cells were geneti-
`cally engineered in a lab to proliferate inside
`their bodies and seek and destroy cancer. The
`
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`Experimenting. A life of twists and turns has Carl
`June pressing forward with a radical cancer therapy.
`
`NEWSFOCUS
`
`not how T cell treatment works. Every batch
`is a distinctive drug, and right now, every
`step toward making it holds the chance of
`human error.
`As academic cancer researchers and com-
`panies work to expand the therapy’s reach,
`June and his colleagues are in the public eye.
`Along with the accolades are
`critics charging that they’ve
`claimed more than their share
`of scientific credit and law-
`suits alleging violations in
`agreements with collabora-
`tors. They are deeply driven to
`save lives; cancer looms large
`in June’s own autobiography. But at stake,
`too, for the researchers and their institu-
`tion, is money and scientifi c glory, and the
`chance to combat cancer with immunology
`on a grand scale.
`
`Online
`
`sciencemag.org
`Podcast interview
`with author Jennifer
`Couzin-Frankel (http://
`scim.ag/pod_6140).
`
`Porter was en route to vacation in western
`Maryland with his family when the embargo
`lifted. His phone started ringing. “I was in
`the car for 8 hours that day,” he says. “I spent
`8 hours straight on my phone,
`answering e-mail, answering phone
`calls. It was a story that took us all by
`surprise. It kind of went viral.” June
`fi elded 5000 requests from patients
`and their families for the therapy.
`Eight hundred media outlets world-
`wide covered the story.
`NCI reversed course and awarded June’s
`team nearly $500,000 a year for 4 years, in
`part to create engineered T cells for patients.
`Pharmaceutical companies began courting
`June and his colleagues. Almost exactly
`a year after publication, Novartis signed a
`multimillion dollar agreement with Penn,
`licensing rights to the therapy with the goal
`of getting it approved by drug regulators.
`Three patients, two of them still in remis-
`sion today, proved to be the tipping point that
`June had imagined.
`Two years later, nearly all of the thousands
`of cancer patients desperate for engineered T
`cells are a long way from getting them. For
`one, the therapy can tackle only a subset of
`blood cancers, and it remains highly experi-
`mental. About three dozen people at Penn
`have received it, along with more than 50 else-
`where. Not everyone is helped, and many of
`those who are suffer serious side effects. In
`those whose disease has disappeared, no one
`knows yet how long the calm will last. “The
`medical literature is just littered with exam-
`ples of drugs that look great on your first
`10 patients, and they don’t pan out for
`one reason or another,” Porter says.
`History may urge caution, but
`it’s hard not to be swept up in the
`moment. Despite the small numbers,
`many oncologists believe that what
`June’s team and others now replicat-
`ing it have seen is unprecedented.
`No cell therapy has proliferated in
`the body, endured, and slain cancer
`quite like this one.
`A looming question now is how to move
`engineered T cell therapy forward—how to
`test it in more patients, at more centers, in
`different forms of cancer. Drug companies
`“don’t care if it costs $500 million to develop
`the fi rst vial, as long as you can make the sec-
`ond vial for $1,” says Steven Rosenberg, an
`NCI surgical oncologist in Bethesda, Mary-
`land, who’s spent decades developing cell
`therapies. As Rosenberg knows well, that’s
`
`T cells remodeled
`The backbone of June’s work was forged in
`the mid-1980s by an Israeli immunologist.
`Zelig Eshhar was on sabbatical in Palo Alto,
`California, when he began toying with an
`unorthodox question: whether T cells, the sen-
`tries of the immune system, could be coaxed to
`destroy different targets. To accomplish this,
`Eshhar knew that he needed T cells to recog-
`nize and latch onto molecules that they nor-
`mally ignore. And the only way to make that
`happen was by inserting foreign DNA into
`T cells, to alter the receptors they produced.
`Eshhar returned home to the Weizmann
`Institute of Science in Rehovot, Israel, and
`got to work. Failure after failure followed. The
`technology to insert DNA was rudimentary.
`Then, in the late 1980s, Eshhar triumphed,
`adding a combination of gene sequences
`
`“ We knew something worked. …
`We knew it wasn’t an accident.”
`
`—CARL JUNE,
`ABRAMSON CANCER CENTER
`UNIVERSITY OF PENNSYLVANIA
`
`into a type of immortalized T cell that more
`readily accepts foreign DNA and endow-
`ing the cells with new targets they could kill.
`“The moment we realized it was working …
`we became, I don’t want to say obsessed, but
`really invested,” he recalls.
` Eshhar’s feat was only the first step.
`To treat a disease like cancer, researchers
`needed to identify protein targets unique to
`certain tumor cells—otherwise, the modi-
`
`didn’t have. “We basically decided that we
`would just publish with three patients,” June
`says. Getting the word out, he hoped, could
`shift the dynamic in their favor. Porter was
`game to try, but skeptical that any reputable
`journal would accept a paper with an n of 3.
`He turned out to be wrong. The New
`England Journal of Medicine welcomed a
`report about Olson and his mouse dose of
`T cells. Science Translational Medicine,
`Science’s sister journal, snapped up a manu-
`script detailing all three patients. The papers
`were published simultaneously on 10 August
`2011. The university put out a news release
`that day. Its title: “Genetically Modified
`‘Serial Killer’ T Cells Obliterate Tumors in
`Patients with Chronic Lymphocytic Leuke-
`mia, Penn Researchers Report.”
`
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`
`fi ed T cells would destroy healthy tissue, too.
`They also had to ensure that the cells multi-
`plied inside the body and persisted, wiping
`out every trace of cancer and preventing it
`from coming back.
`Slowly, a handful of researchers picked
`up on Eshhar’s accomplishment and car-
`ried it forward. At Memorial Sloan-Ketter-
`ing Cancer Center in New York City, cell
`therapist and oncologist Michel Sadelain
`set to work introducing genes into human T
`cells. “It took me 3, 4 years to better trans-
`fer genes into more than 0.5%
`of the culture,” Sadelain says.
`“Today, we can take a high
`school kid [and] in an after-
`noon, they know how to take
`T cells and blast genes in all
`of them.” Sadelain pushed for
`a name, and “chimeric anti-
`gen receptor” cells, or simply
`CAR cells, stuck.
`While Sadelain focused on
`cancer from the start, June got
`there circuitously. His career
`trajectory tracked Cold War
`history, and the reason for that
`was Vietnam. In 1971, when
`he was 18, a lottery gave June
`a near-certain chance of being
`drafted. He abandoned plans
`to enroll at Stanford University
`and applied to the U.S. Naval
`Academy in Annapolis, Mary-
`land. The war ended 2 years
`later, but June remained with
`the military, which financed
`his medical education. With
`fears of nuclear attacks run-
`ning high, he trained as an
`oncologist and a bone mar-
`row transplanter to treat those
`exposed to high doses of radia-
`tion. In 1989, the Berlin Wall
`collapsed. The Cold War ended
`soon after. The military “didn’t
`care about bone marrow trans-
`plants after that,” June says. He
`needed a new passion.
` T h e N av y d i d n ’t f u n d c a n c e r
`research, so June, then at the Naval Med-
`ical Research Institute in Bethesda,
`turned to HIV. The decision proved pre-
`scient, as he learned the ins and outs of
`T cells and the immune system, knowledge
`that would later serve him well. He spent a
`decade training T cells to fl ourish in HIV
`patients, whose own T cells are destroyed
`by the virus. An immunologist in the lab,
`Bruce Levine, explored how to grow T cells
`and what signals could best “activate” them,
`
`2001, shortly after her husband left the Navy
`and the family relocated to Philadelphia. Their
`daughter was 9 years old. “It took a long time
`to recover,” he says, speaking slowly as he
`thinks back on those years. “A lot of people
`helped me out.”
`The ripples hit those around June, too.
`“We knew Cindy, we had socialized with
`her,” Levine says. “We saw what happened
`and what it did to Carl. Those are hugely
`signifi cant events for people, and also for
`the program.”
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`CREDIT: PEGGY PETERSON PHOTOGRAPHY/PENN MEDICINE
`
`Advances and acrimony
`At Penn, June continued his HIV work but
`also threw himself into cancer, motivated
`by his wife’s death and by a belief that the
`pieces were falling into place to successfully
`treat patients with CAR cells at last. He was
`enthusiastically welcomed by two oncol-
`ogists: Porter, who cares for adults with
`blood cancer at Penn’s Abramson Cancer
`Center, and Stephan Grupp with the Chil-
`dren’s Hospital of Philadelphia (CHOP),
`who showed up at June’s offi ce door one day
`and asked to collaborate.
`A handful of research-
`ers elsewhere were also
`in the race to bring CAR
`therapy to people. In addi-
`tion to June, they included
`Sadelain at Sloan-Ketter-
`ing, Rosenberg at NCI, and
`Malcolm Brenner at Baylor
`College of Medicine in Hous-
`ton, Texas. All were converg-
`ing on the same cancer target,
`a marker called CD19. The
`only cells sporting CD19 are
`B cells, which proliferate dan-
`gerously in B cell leukemias.
`This was valuable for two rea-
`sons. The marker was a prom-
`ising bull’s-eye, because it was
`all but universal on these can-
`cer cells. And although B cells
`are an important component
`of the immune system, they
`are not needed for survival—
`which was reassuring, because
`attacking CD19 would surely
`destroy healthy B cells, too.
`How to design the very
`best CAR against CD19
`was the big question. CARs
`“come in multiple flavors,”
`Sadelain says. There are dif-
`ferent ways to engineer a new
`receptor that will latch on to
`CD19. One important ingre-
`dient is the “co-stimulatory
`signal,” which is embedded
`in the CAR cells to activate them and keep
`them alive in a patient. Sadelain’s group, like
`the others, studied a slew of possibilities in
`mice and settled on one, called CD28, which
`looked the most promising. Rosenberg and
`groups at two other centers picked CD28 as
`well. All four had clinical trials up and run-
`ning when June’s trial opened.
`June chose a different co-stimulatory
`signal, called 4-1BB, in part to distinguish
`his efforts and also because lab studies sug-
`gested that it helped T cells proliferate. It
`
`turning them on outside the body to help
`them destroy their targets.
`Then in 1995, June’s personal and pro-
`fessional lives abruptly converged. His wife
`Cynthia was diagnosed with ovarian cancer.
`The couple had a 3-year-old daughter and two
`teenage sons. “I saw for the fi rst time what it
`was like to be on the other side of the bed,”
`he says. June was a believer in manipulating
`the immune system to treat cancer, but suit-
`able immunotherapies weren’t ripe at the time.
`Cynthia June was 46 when she died in
`
`Cautious optimist.
`Oncologist David Porter
`hopes that early results
`will hold up as more
`patients are treated.
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`was a strong candidate in mice but not quite
`as impressive as CD28. A group at St. Jude
`Children’s Research Hospital in Memphis,
`Tennessee, led by an oncologist named Dario
`Campana, had designed the fi rst CAR con-
`struct with 4-1BB. Unlike the other groups,
`June’s also used a disabled HIV virus to
`genetically engineer the T cells and a differ-
`ent recipe for growing them in the lab.
`As it turned out, combatting cancer was in
`the details. The fi rst to publish an anti-CD19
`CAR therapy success was Rosenberg’s team
`in 2010. They used the CD28 strategy, and one
`patient with a form of lymphoma achieved a
`long-lasting partial remission. But it was
`Penn’s results in the three men with leukemia,
`with a 4-1BB CAR, that transfi xed the cancer
`community and the wider world.
`“It made a believer out of a lot of peo-
`ple who were pretty skeptical,” says Ravi
`Bhatia, who treats blood cancers at City of
`Hope in Duarte, California, and counts him-
`self among past doubters. His own hospi-
`tal had been studying CAR cell therapy for
`several years, but there and elsewhere the
`transplanted T cells had quickly disappeared
`from the bloodstream. “That,” Bhatia says,
`“was a big concern.”
`June, Porter, Levine, and Grupp—who
`was gearing up to treat the fi rst children—
`sought to stay anchored amid the hype. “You
`try and keep your feet on the ground and say,
`‘We still have work to do,’ ” Levine says.
`The competition was fi erce and not always
`friendly. In the pages of The New England
`Journal of Medicine, Rosenberg’s group and
`June’s sparred over whether Rosenberg’s
`CAR therapy success, published 12 months
`before June’s, was due
`to engineered T cells or
`attributable to chemo-
`therapy that the patient
`received fi rst, to make
`room for new cells.
`“There’s acrimony out
`there,” Sadelain says.
`The most bitter
`came in July 2012. St.
`Jude sued the trustees of
`the University of Pennsylvania for breaching
`materials transfer agreements signed with St.
`Jude in 2003 and 2007, when Campana had
`shared his CAR materials with June.
`Penn shot back with a lawsuit of its own,
`arguing that June’s CAR cell construct was
`different than Campana’s. Less than 3 weeks
`after that suit, in August 2012, Novartis and
`Penn unveiled an alliance to commercialize
`the T cell treatment. The company said that it
`would devote $20 million to build a cell ther-
`apy research center at the university.
`
`“ You try and keep your
`feet on the ground
`and say, ‘We still
`have work to do.’”
`
`Jumping the hurdles
`That collaboration is now moving swiftly
`ahead. At Novartis, dozens of people are strat-
`egizing over how to manufacture personalized
`T cells for patients. Novartis needs to deter-
`mine how long the cells can hold up outside
`the body, because that determines how many
`costly cell-processing
`facilities the company
`must open worldwide.
`It has to automate its
`method of growing
`and manipulating the
`cells as much as possi-
`ble to reduce costs and
`the chance of human
`error. It has to consider
`whether the time from
`“vein to vein,” when the cells are removed
`until they’re put back in, can be shortened.
`It now stands at about 3 weeks.
`“All of this has to be thought through
`very carefully, not only for the U.S. but also
`on a global scale,” says Manuel Litchman,
`who is overseeing the therapy’s develop-
`ment program for Novartis Oncology. In the
`cramped lab at Penn, Levine is busy train-
`ing Novartis employees. Company offi cials
`meet several times a week with June’s team.
`In December, Novartis paid $43 million for
`
`—BRUCE LEVINE,
`
`UNIVERSITY OF PENNSYLVANIA
`
`In the months that followed, the legal
`dueling continued. Then in March of
`this year came a turning point: St. Jude’s
`application for a patent on Campana’s T cell
`construct, with its 4-1BB signaling domain,
`was approved.
`Three days later, Penn sued St. Jude
`again, claiming that the Campana patent
`was invalid. That law-
`suit exposed an under-
`cur rent of concern
`over who owned what.
`Penn’s lawyers are seek-
`ing “a judicial determi-
`nation” that they are
`not infringing on the St.
`Jude patent.
`Neither June nor
`Campana, who is now
`at the National Uni-
`versity of Singapore,
`would comment on
`the lawsuits. Novar-
`tis spokesman Scott
`Young wouldn’t say
`much either—the company is not a party
`to any of the three suits—but he stressed in
`an e-mail message that “we have complete
`confi dence in the viability of our collabora-
`tion with UPenn.”
`
`“ The medical litera-
`ture is just littered
`with examples of
`drugs that look
`great on your fi rst
`10 patients, and
`they don’t pan out.”
`
`—DAVID PORTER,
`
`ABRAMSON CANCER CENTER
`
`UNIVERSITY OF PENNSYLVANIA
`
`an immunotherapy manufacturing facility in
`Morris Plains, New Jersey, which had been
`owned by a company, Dendreon, making a
`prostate cancer vaccine. “It’s not going to
`look that different in Morris Plains than it
`looks in Bruce’s lab,” Litchman says. “It’s
`just going to be replicated many, many
`times over, to fi ll up the suites there.”
`One top priority is
`consistency. Every batch
`of T cells will be differ-
`ent because each origi-
`nates with a different
`patient. But other scien-
`tifi c and manufacturing
`variables—the vector
`that inserts the foreign
`DNA, techniques to
`grow the cells, how
`they’re transported—
`can make the outcome
`unpredictable.
`June’s group learned
`this the hard way: After
`the fanfare around their
`fi rst three patients, they treated three more
`in January 2012 with a new vector lot. None
`responded. “I was just stumped out to the
`max,” June says. He had no idea what had
`happened and still can’t say whether some-
`thing went awry with the vector material or
`whether the outcome was due to random fl uc-
`tuations in the therapy’s success. “All we knew
`was, it worked three times, and then it didn’t
`work three times.” All three of those patients
`later died of their disease.
`Next in line was patient 7, who turned
`out to be another roller coaster. She was
`Emily Whitehead, a 6-year-old with end-
`stage leukemia whose parents turned to
`June’s cell therapy as a last-ditch hope.
`The experimental treatment sent her body
`into a deadly immune overdrive. She spent
`2 weeks on a ventilator in the CHOP intensive
`care unit while doctors tried everything they
`could think of to save her.
`“We thought it was over,” June says. He
`drafted an e-mail message to Penn’s provost:
`“It is with regret that I inform you that our
`fi rst pediatric patient on the CART19 trial will
`likely die,” he wrote. “There is nothing to do
`at this point other than hope for a miracle.”
`June pledged to “conduct a full investigation.”
`It turned out that he didn’t need to, and the
`e-mail was left unsent.
`As doctors parsed Emily’s lab results,
`they found that her revved up T cells were
`causing overproduction of a molecule called
`interleukin-6. She was saved, in a tale that
`became hospital lore, by an arthritis drug that
`disables it. June knew about the drug only
`
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`For every T cell infused, between 1000
`and 93,000 leukemia cells die, showing just
`how dramatically the engineered T cells are
`multiplying inside the body. The group is
`still studying why their T cells proliferate
`like this, although they suspect that it’s partly
`due to the 4-1BB construct that Campana
`pioneered. As expected, healthy B cells are
`destroyed, and the long-term effects of that
`remain uncertain. The expense of CAR treat-
`ment has plunged, but it still costs $20,000
`to $40,000 to generate the cells. That doesn’t
`include supportive care in the hospital after
`patients receive them.
`In March, Sadelain reported on fi ve patients
`with acute leukemia in Science Translational
`Medicine. That disease is more aggressive
`than chronic leukemia in adults, and oncolo-
`gists were heartened by what they read: Four
`of the patients went into remission, a neces-
`sary precursor to getting a bone marrow trans-
`plant, which they then received. Three are still
`alive at least 5 months after treatment. “That
`it was verifi ed at another center, at Memorial,
`was very important,” says Bhatia at the City of
`Hope. It was “not just something strange that
`happened” in the people treated at Penn.
`Still, physicians like Porter and Grupp are
`mindful that this isn’t life-changing for every-
`one. “When I’m doing informed consent with
`these families, the fi rst thing I say is, ‘Forget
`everything you’ve read about this,’ ” Grupp
`says. “Nothing could possibly be as promis-
`ing as the various articles about this make it
`seem.” Only four people, including Emily,
`have been followed for more than a year. A
`looming question is whether CAR therapy can
`work in solid tumors, and June and others are
`opening clinical trials to try and fi nd out.
`Nearly 3 years after the summer that
`changed everything, the Penn group is
`still working fl at out to keep up: enrolling
`as many patients on the trials as they can,
`working with drug regulators to discuss how
`best to study the cells with an eye toward
`approval, collaborating with Novartis to
`train their employees and streamline the
`cell-generating process. “I’m tired,” say s
`Porter, and he sounds it. June, a serious bike
`racer and runner, has scaled back his hobby,
`though he did manage to fit in a 34-mile
`ultramarathon last weekend. “I didn’t used
`to work as many hours as I do” now, he says.
`“I mean, I used to work, but I’d take more
`time off.” He’s eagerly waiting for the hand-
`off, the day when Novartis starts process-
`ing T cells and making CARs. Neither June
`nor Novartis can say when that will be, but
`for June, it will mark a return to normalcy.
`“Until then,” he says, “it’s overdrive.”
`–JENNIFER COUZIN-FRANKEL
`
`CREDIT: KARI WHITEHEAD
`
`NEWSFOCUS
`
`Survivor. Eight-year-old
`Emily Whitehead was the
`fi rst child on the experi-
`mental Penn protocol,
`and she’s now cancer-
`free 1 year later.
`
`because his daughter Sarah had been diag-
`nosed with rheumatoid arthritis shortly after
`her mother’s death. Grupp happened upon it
`independently, when a colleague found it by
`Googling on his iPhone.
`Emily remains in remission more than
`1 year later, her hair long enough now for
`pigtails and her 8th birthday
`behind her. In her DNA, Grupp
`discovered a gene mutation that
`predisposes to a hyperactive
`immune response, which could
`help explain why the therapy
`sickened her as it did. Grupp has
`since switched to giving other
`children a tenth of the T cell dose
`that Emily received, although “in
`my heart of hearts I’m not sure the
`dose matters that much,” because
`the cells multiply with aban-
`don inside the body. All those
`on the Penn trial became deeply
`attached to Emily after her har-
`rowing experience. Levine dis-
`plays pictures of her in his offi ce. June, who
`remarried and now has a 10-year-old daugh-
`ter of his own, chokes up when he speaks of
`Emily and her family.
`For the Penn team, Emily and the other
`patients are teaching laboratories, showing
`what the engineered T cells can do. “I’ve
`never been involved in anything like this in
`my life,” Grupp says. In addition to the crush
`of media attention and hundreds of inqui-
`
`ries from patients and families, Grupp was
`taken aback by parents reporting their child’s
`progress on Facebook before he’d shared
`the news with the wider scientifi c world. “I
`am in a position of having my results pub-
`licly disclosed without having them subject
`to peer review,” he says. “That’s the aspect of
`
`“ When I’m doing informed
`consent with these families,
`the fi rst thing I say is, ‘Forget
`everything you’ve read about
`this.’ Nothing could possibly
`be as promising as the various
`articles about this make it seem.”
`
`CHILDREN’S HOSPITAL OF PHILADELPHIA
`
`—STEPHAN GRUPP,
`
`this I was least prepared for,” and it’s one that
`makes him “extremely uncomfortable.”
`Grupp has treated 14 children with acute
`lymphoblastic leukemia so far. Of the fi ve
`reported at scientifi c meetings or published,
`four went into remission but one of those later
`relapsed. Porter’s most recent data on adults,
`presented at a meeting in May, includes 10
`responders out of 17 treated, with fi ve of those
`in complete remission for at least 3 months.
`
`1518
`
`28 JUNE 2013 VOL 340 SCIENCE www.sciencemag.org
`Published by AAAS
`
`UPenn Ex. 2015
`Miltenyi v. UPenn
`IPR2022-00855
`
`