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`A Breakthrough Against Leukemia Using Altered T-Cells - The New York Times
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`https://www.nytimes.com/2012/12/10/health/a-breakthrough-against-leukemia-using-altered-t-cells.html
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`In Girlʼs Last Hope, Altered Immune Cells Beat Leukemia
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`By Denise Grady
`Dec. 9, 2012
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`PHILIPSBURG, Pa. — Emma Whitehead has been bounding around the house lately, practicing somersaults and rugby-style tumbles that
`make her parents wince.
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`It is hard to believe, but last spring Emma, then 6, was near death from leukemia. She had relapsed twice after chemotherapy, and doctors
`had run out of options.
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`Desperate to save her, her parents sought an experimental treatment at the Children’s Hospital of Philadelphia, one that had never before
`been tried in a child, or in anyone with the type of leukemia Emma had. The experiment, in April, used a disabled form of the virus that
`causes AIDS to reprogram Emma’s immune system genetically to kill cancer cells.
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`The treatment very nearly killed her. But she emerged from it cancer-free, and about seven months later is still in complete remission. She
`is the first child and one of the first humans ever in whom new techniques have achieved a long-sought goal — giving a patient’s own
`immune system the lasting ability to fight cancer.
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`Emma had been ill with acute lymphoblastic leukemia since 2010, when she was 5, said her parents, Kari and Tom. She is their only child.
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`She is among just a dozen patients with advanced leukemia to have received the experimental treatment, which was developed at the
`University of Pennsylvania. Similar approaches are also being tried at other centers, including the National Cancer Institute and Memorial
`Sloan-Kettering Cancer Center in New York.
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`“Our goal is to have a cure, but we can’t say that word,” said Dr. Carl June, who leads the research team at the University of Pennsylvania.
`He hopes the new treatment will eventually replace bone-marrow transplantation, an even more arduous, risky and expensive procedure
`that is now the last hope when other treatments fail in leukemia and related diseases.
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`Three adults with chronic leukemia treated at the University of Pennsylvania have also had complete remissions, with no signs of disease;
`two of them have been well for more than two years, said Dr. David Porter. Four adults improved but did not have full remissions, and one
`was treated too recently to evaluate. A child improved and then relapsed. In two adults, the treatment did not work at all. The
`Pennsylvania researchers were presenting their results on Sunday and Monday in Atlanta at a meeting of the American Society of
`Hematology.
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`Despite the mixed results, cancer experts not involved with the research say it has tremendous promise, because even in this early phase
`of testing it has worked in seemingly hopeless cases. “I think this is a major breakthrough,” said Dr. Ivan Borrello, a cancer expert and
`associate professor of medicine at the Johns Hopkins University School of Medicine.
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`Dr. John Wagner, the director of pediatric blood and marrow transplantation at the University of Minnesota, called the Pennsylvania
`results “phenomenal” and said they were “what we’ve all been working and hoping for but not seeing to this extent.”
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`A major drug company, Novartis, is betting on the Pennsylvania team and has committed $20 million to building a research center on the
`university’s campus to bring the treatment to market.
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`Hervé Hoppenot, the president of Novartis Oncology, called the research “fantastic” and said it had the potential — if the early results held
`up — to revolutionize the treatment of leukemia and related blood cancers. Researchers say the same approach, reprogramming the
`patient’s immune system, may also eventually be used against tumors like breast and prostate cancer.
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`To perform the treatment, doctors remove millions of the patient’s T-cells — a type of white blood cell — and insert new genes that enable
`the T-cells to kill cancer cells. The technique employs a disabled form of H.I.V. because it is very good at carrying genetic material into T-
`cells. The new genes program the T-cells to attack B-cells, a normal part of the immune system that turn malignant in leukemia.
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`The altered T-cells — called chimeric antigen receptor cells — are then dripped back into the patient’s veins, and if all goes well they
`multiply and start destroying the cancer.
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`The T-cells home in on a protein called CD-19 that is found on the surface of most B-cells, whether they are healthy or malignant.
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`A sign that the treatment is working is that the patient becomes terribly ill, with raging fevers and chills — a reaction that oncologists call
`“shake and bake,” Dr. June said. Its medical name is cytokine-release syndrome, or cytokine storm, referring to the natural chemicals that
`pour out of cells in the immune system as they are being activated, causing fevers and other symptoms. The storm can also flood the lungs
`and cause perilous drops in blood pressure — effects that nearly killed Emma.
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`https://www.nytimes.com/2012/12/10/health/a-breakthrough-against-leukemia-using-altered-t-cells.html
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`A Breakthrough Against Leukemia Using Altered T-Cells - The New York Times
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`Steroids sometimes ease the reaction, but they did not help Emma. Her temperature hit 105. She wound up on a ventilator, unconscious
`and swollen almost beyond recognition, surrounded by friends and family who had come to say goodbye.
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`But at the 11th hour, a battery of blood tests gave the researchers a clue as to what might help save Emma: her level of one of the
`cytokines, interleukin-6 or IL-6, had shot up a thousandfold. Doctors had never seen such a spike before and thought it might be what was
`making her so sick.
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`Dr. June knew that a drug could lower IL-6 — his daughter takes it for rheumatoid arthritis. It had never been used for a crisis like
`Emma’s, but there was little to lose. Her oncologist, Dr. Stephan A. Grupp, ordered the drug. The response, he said, was “amazing.”
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`Within hours, Emma began to stabilize. She woke up a week later, on May 2, the day she turned 7; the intensive-care staff sang “Happy
`Birthday.”
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`Since then, the research team has used the same drug, tocilizumab, in several other patients.
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`In patients with lasting remissions after the treatment, the altered T-cells persist in the bloodstream, though in smaller numbers than
`when they were fighting the disease. Some patients have had the cells for years.
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`Dr. Michel Sadelain, who conducts similar studies at the Sloan-Kettering Institute, said: “These T-cells are living drugs. With a pill, you
`take it, it’s eliminated from your body and you have to take it again.” But T-cells, he said, “could potentially be given only once, maybe only
`once or twice or three times.”
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`The Pennsylvania researchers said they were surprised to find any big drug company interested in their work, because a new batch of T-
`cells must be created for each patient — a far cry from the familiar commercial strategy of developing products like Viagra or cholesterol
`medicines, in which millions of people take the same drug.
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`But Mr. Hoppenot said Novartis was taking a different path with cancer drugs, looking for treatments that would have a big, unmistakable
`impact on a small number of patients. Such home-run drugs can be approved more quickly and efficiently, he said, with smaller studies
`than are needed for drugs with less obvious benefits.
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`“The economic model is totally acceptable,” Mr. Hoppenot said.
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`But such drugs tend to be extremely expensive. A prime example is the Novartis drug Gleevec, which won rapid approval in 2001 for use
`against certain types of leukemia and gastrointestinal tumors. It can cost more than $5,000 a month, depending on the dosage.
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`Dr. June said that producing engineered T-cells costs about $20,000 per patient — far less than the cost of a bone-marrow transplant.
`Scaling up the procedure should make it even less expensive, he said, but he added, “Our costs do not include any profit margin, facility
`depreciation costs or other clinical care costs, and other research costs.”
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`The research is still in its early stages, and many questions remain. The researchers are not entirely sure why the treatment works, or
`why it sometimes fails. One patient had a remission after being treated only twice, and even then the reaction was so delayed that it took
`the researchers by surprise. For the patients who had no response whatsoever, the team suspects a flawed batch of T-cells. The child who
`had a temporary remission apparently relapsed because not all of her leukemic cells had the marker that was targeted by the altered T-
`cells.
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`It is not clear whether a patient’s body needs the altered T-cells forever. The cells do have a drawback: they destroy healthy B-cells as well
`as cancerous ones, leaving patients vulnerable to certain types of infections, so Emma and the other patients need regular treatments with
`immune globulins to prevent illness.
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`So far, her parents say, Emma seems to have taken it all in stride. She went back to school this year with her second-grade classmates, and
`though her grades are high and she reads about 50 books a month, she insists impishly that her favorite subjects are lunch and recess.
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`“It’s time for her to be a kid again and get her childhood back,” Mr. Whitehead said.
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`https://www.nytimes.com/2012/12/10/health/a-breakthrough-against-leukemia-using-altered-t-cells.html
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`2/2
`
`UPenn Ex. 2005
`Miltenyi v. UPenn
`IPR2022-00855
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