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`Immune System, Loaded With Remade T-cells, Vanquishes Cancer - The New York Times
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`https://www.nytimes.com/2011/09/13/health/13gene.html
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`An Immune System Trained to Kill Cancer
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`By Denise Grady
`Sept. 12, 2011
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`PHILADELPHIA — A year ago, when chemotherapy stopped working against his leukemia, William Ludwig signed up to be the first
`patient treated in a bold experiment at the University of Pennsylvania. Mr. Ludwig, then 65, a retired corrections officer from Bridgeton,
`N.J., felt his life draining away and thought he had nothing to lose.
`
`Doctors removed a billion of his T-cells — a type of white blood cell that fights viruses and tumors — and gave them new genes that would
`program the cells to attack his cancer. Then the altered cells were dripped back into Mr. Ludwig’s veins.
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`At first, nothing happened. But after 10 days, hell broke loose in his hospital room. He began shaking with chills. His temperature shot up.
`His blood pressure shot down. He became so ill that doctors moved him into intensive care and warned that he might die. His family
`gathered at the hospital, fearing the worst.
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`A few weeks later, the fevers were gone. And so was the leukemia.
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`There was no trace of it anywhere — no leukemic cells in his blood or bone marrow, no more bulging lymph nodes on his CT scan. His
`doctors calculated that the treatment had killed off two pounds of cancer cells.
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`A year later, Mr. Ludwig is still in complete remission. Before, there were days when he could barely get out of bed; now, he plays golf and
`does yard work.
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`“I have my life back,” he said.
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`Mr. Ludwig’s doctors have not claimed that he is cured — it is too soon to tell — nor have they declared victory over leukemia on the basis
`of this experiment, which involved only three patients. The research, they say, has far to go; the treatment is still experimental, not
`available outside of studies.
`
`But scientists say the treatment that helped Mr. Ludwig, described recently in The New England Journal of Medicine and Science
`Translational Medicine, may signify a turning point in the long struggle to develop effective gene therapies against cancer. And not just for
`leukemia patients: other cancers may also be vulnerable to this novel approach — which employs a disabled form of H.I.V.-1, the virus that
`causes AIDS, to carry cancer-fighting genes into the patients’ T-cells. In essence, the team is using gene therapy to accomplish something
`that researchers have hoped to do for decades: train a person’s own immune system to kill cancer cells.
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`Two other patients have undergone the experimental treatment. One had a partial remission: his disease lessened but did not go away
`completely. Another had a complete remission. All three had had advanced chronic lymphocytic leukemia and had run out of
`chemotherapy options. Usually, the only hope for a remission in such cases is a bone-marrow transplant, but these patients were not
`candidates for it.
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`Dr. Carl June, who led the research and directs translational medicine in the Abramson Cancer Center at the University of Pennsylvania,
`said that the results stunned even him and his colleagues, Dr. David L. Porter, Bruce Levine and Michael Kalos. They had hoped to see
`some benefit but had not dared dream of complete, prolonged remissions. Indeed, when Mr. Ludwig began running fevers, the doctors did
`not realize at first that it was a sign that his T-cells were engaged in a furious battle with his cancer.
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`https://www.nytimes.com/2011/09/13/health/13gene.html
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`Immune System, Loaded With Remade T-cells, Vanquishes Cancer - The New York Times
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`Tiny magnetic beads force the larger T-cells to divide before they are infused into the
`patient. University of Pennsylvania
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`Other experts in the field said the results were a major advance.
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`“It’s great work,” said Dr. Walter J. Urba of the Providence Cancer Center and Earle A. Chiles Research Institute in Portland, Ore. He
`called the patients’ recoveries remarkable, exciting and significant. “I feel very positive about this new technology. Conceptually, it’s very,
`very big.”
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`Dr. Urba said he thought the approach would ultimately be used against other types of cancer as well as leukemia and lymphoma. But he
`cautioned, “For patients today, we’re not there yet.” And he added the usual scientific caveat: To be considered valid, the results must be
`repeated in more patients, and by other research teams.
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`Dr. June called the techniques “a harvest of the information from the molecular biology revolution over the past two decades.”
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`Hitting a Genetic Jackpot
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`To make T-cells search out and destroy cancer, researchers must equip them to do several tasks: recognize the cancer, attack it, multiply,
`and live on inside the patient. A number of research groups have been trying to do this, but the T-cells they engineered could not
`accomplish all the tasks. As a result, the cells’ ability to fight tumors has generally been temporary.
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`The University of Pennsylvania team seems to have hit all the targets at once. Inside the patients, the T-cells modified by the researchers
`multiplied to 1,000 to 10,000 times the number infused, wiped out the cancer and then gradually diminished, leaving a population of
`“memory” cells that can quickly proliferate again if needed.
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`The researchers said they were not sure which parts of their strategy made it work — special cell-culturing techniques, the use of H.I.V.-1
`to carry new genes into the T-cells, or the particular pieces of DNA that they selected to reprogram the T-cells.
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`The concept of doctoring T-cells genetically was first developed in the 1980s by Dr. Zelig Eshhar at the Weizmann Institute of Science in
`Rehovot, Israel. It involves adding gene sequences from different sources to enable the T-cells to produce what researchers call chimeric
`antigen receptors, or CARs — protein complexes that transform the cells into, in Dr. June’s words, “serial killers.”
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`Mr. Ludwig’s disease, chronic lymphocytic leukemia is a cancer of B-cells, the part of the immune system that normally produces
`antibodies to fight infection. All B-cells, whether healthy or leukemic, have on their surfaces a protein called CD19. To treat patients with
`the disease, the researchers hoped to reprogram their T-cells to find CD19 and attack B-cells carrying it.
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`But which gene sequences should be used to reprogram the T-cells, from which sources? And how do you insert them?
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`https://www.nytimes.com/2011/09/13/health/13gene.html
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`Immune System, Loaded With Remade T-cells, Vanquishes Cancer - The New York Times
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`FULL OF LIFE William Ludwig, 66, in his RV parked at his home in New Jersey. Jessica
`Kourkounis for The New York Times
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`Various research groups have used different methods. Viruses are often used as carriers (or vectors) to insert DNA into other cells
`because that kind of genetic sabotage is exactly what viruses normally specialize in doing. To modify their patients’ T-cells, Dr. June and
`his colleagues tried a daring approach: they used a disabled form of H.I.V.-1. They are the first ever to use H.I.V.-1 as the vector in gene
`therapy for cancer patients (the virus has been used in other diseases).
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`The AIDS virus is a natural for this kind of treatment, Dr. June said, because it evolved to invade T-cells. The idea of putting any form of
`the AIDS virus into people sounds a bit frightening, he acknowledged, but the virus used by his team was “gutted” and was no longer
`harmful. Other researchers had altered and disabled the virus by adding DNA from humans, mice and cows, and from a virus that infects
`woodchucks and another that infects cows. Each bit was chosen for a particular trait, all pieced together into a vector that Dr. June called
`a “Rube Goldberg-like solution” and “truly a zoo.”
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`“It incorporates the ability of H.I.V. to infect cells but not to reproduce itself,” he said.
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`To administer the treatment, the researchers collected as many of the patients’ T-cells as they could by passing their blood through a
`machine that removed the cells and returned the other blood components back into the patients’ veins. The T-cells were exposed to the
`vector, which transformed them genetically, and then were frozen. Meanwhile, the patients were given chemotherapy to deplete any
`remaining T-cells, because the native T-cells might impede the growth of the altered ones. Finally, the T-cells were infused back into the
`patients.
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`Then, Dr. June said, “The patient becomes a bioreactor” as the T-cells proliferate, pouring out chemicals called cytokines that cause fever,
`chills, fatigue and other flulike symptoms.
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`The treatment wiped out all of the patients’ B-cells, both healthy ones and leukemic ones, and will continue to do for as long as the new T-
`cells persist in the body, which could be forever (and ideally should be, to keep the leukemia at bay). The lack of B-cells means that the
`patients may be left vulnerable to infection, and they will need periodic infusions of a substance called intravenous immune globulin to
`protect them.
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`So far, the lack of B-cells has not caused problems for Mr. Ludwig. He receives the infusions every few months. He had been receiving
`them even before the experimental treatment because the leukemia had already knocked out his healthy B-cells.
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`One thing that is not clear is why Patient 1 and Patient 3 had complete remissions, and Patient 2 did not. The researchers said that when
`Patient 2 developed chills and fever, he was treated with steroids at another hospital, and the drugs may have halted the T-cells’ activity.
`But they cannot be sure. It may also be that his disease was too severe.
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`The researchers wrote an entire scientific article about Patient 3, which was published in The New England Journal of Medicine. Like the
`other patients, he also ran fevers and felt ill, but the reaction took longer to set in, and he also developed kidney and liver trouble — a sign
`of tumor lysis syndrome, a condition that occurs when large numbers of cancer cells die off and dump their contents, which can clog the
`kidneys. He was given drugs to prevent kidney damage. He had a complete remission.
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`What the journal article did not mention was that Patient 3 was almost not treated.
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`https://www.nytimes.com/2011/09/13/health/13gene.html
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`Immune System, Loaded With Remade T-cells, Vanquishes Cancer - The New York Times
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`Because of his illness and some production problems, the researchers said, they could not produce anywhere near as many altered T-cells
`for him as they had for the other two patients — only 14 million (“a mouse dose,” Dr. Porter said), versus 1 billion for Mr. Ludwig and 580
`million for Patient 2. After debate, they decided to treat him anyway.
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`MAJOR ADVANCE Dr. Bruce Levine lifted cells from a freezer in his lab in Philadelphia
`last week. Special cell-culturing techniques may have contributed to the lab’s
`success. Jessica Kourkounis for The New York Times
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`Patient 3 declined to be interviewed, but he wrote anonymously about his experience for the University of Pennsylvania Web site. When
`he developed chills and a fever, he said, “I was sure the war was on — I was sure C.L.L. cells were dying.”
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`He wrote that he was a scientist, and that when he was young had dreamed of someday making a discovery that would benefit mankind.
`But, he concluded, “I never imagined I would be part of the experiment.”
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`When he told Patient 3 that he was remission, Dr. Porter said, they both had tears in their eyes.
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`Not Without Danger to Patients
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`While promising, the new techniques developed by the University of Pennsylvania researchers are not without danger to patients.
`Engineered T-cells have attacked healthy tissue in patients at other centers. Such a reaction killed a 39-year-old woman with advanced
`colon cancer in a study at the National Cancer Institute, researchers there reported last year in the journal Molecular Therapy.
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`She developed severe breathing trouble 15 minutes after receiving the T-cells, had to be put on a ventilator and died a few days later.
`Apparently, a protein target on the cancer cells was also present in her lungs, and the T-cells homed in on it.
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`Researchers at Memorial Sloan Kettering Cancer in New York also reported a death last year in a T-cell trial for leukemia (also published
`in Molecular Therapy). An autopsy found that the patient had apparently died from sepsis, not from the T-cells, but because he died just
`four days after the infusion, the researchers said they considered the treatment a possible factor.
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`Dr. June said his team hopes to use T-cells against solid tumors, including some that are very hard to treat, like mesothelioma and ovarian
`and pancreatic cancer. But possible adverse reactions are a real concern, he said, noting that one of the protein targets on the tumor cells
`is also found on membranes that line the chest and abdomen. T-cell attacks could cause serious inflammation in those membranes and
`mimic lupus, a serious autoimmune disease.
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`Even if the T-cells do not hit innocent targets, there are still risks. Proteins they release could cause a “cytokine storm”— high fevers,
`swelling, inflammation and dangerously low blood pressure — which can be fatal. Or, if the treatment rapidly kills billions of cancer cells,
`the debris can damage the kidney and cause other problems.
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`Even if the new T-cell treatment proves to work, the drug industry will be needed to mass produce it. But Dr. June said the research is
`being done only at universities, not at drug companies. For the drug industry to take interest, he said, there will have to be overwhelming
`proof that the treatment is far better than existing ones.
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`“Then I think they’ll jump into it,” he said. “My challenge now is to do this in a larger set of patients with randomization, and to show that
`we have the same effects.”
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`Mr. Ludwig said that when entered the trial, he had no options left. Indeed, Dr. June said that Mr. Ludwig was “almost dead” from the
`leukemia, and the effort to treat him was a “Hail Mary.”
`https://www.nytimes.com/2011/09/13/health/13gene.html
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`7/12/22, 2:05 PM
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`Immune System, Loaded With Remade T-cells, Vanquishes Cancer - The New York Times
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`Mr. Ludwig said: “I don’t recall anybody saying there was going to be a remission. I don’t think they were dreaming to that extent.”
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`The trial was a Phase 1 study, meaning that its main goal was to find out whether the treatment was safe, and at what dose. Of course,
`doctors and patients always hope that there will be some benefit, but that was not an official endpoint.
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`Mr. Ludwig thought that if the trial could buy him six months or a year, it would be worth the gamble. But even if the study did not help
`him, he felt it would still be worthwhile if he could help the study.
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`When the fevers hit, he had no idea that might be a good sign. Instead, he assumed the treatment was not working. But a few weeks later,
`he said that his oncologist, Dr. Alison Loren, told him, “We can’t find any cancer in your bone marrow.”
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`Remembering the moment, Mr. Ludwig paused and said, “I got goose bumps just telling you those words.”
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`“I feel wonderful,” Mr. Ludwig said during a recent interview. “I walked 18 holes on the golf course this morning.”
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`Before the study, he was weak, suffered repeated bouts of pneumonia and was wasting away. Now, he is full of energy. He has gained 40
`pounds. He and his wife bought an R.V., in which they travel with their grandson and nephew. “I feel normal, like I did 10 years before I
`was diagnosed,” Mr. Ludwig said. “This clinical trial saved my life.”
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`Dr. Loren said in an interview, “I hate to say it in that dramatic way, but I do think it saved his life.”
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`Mr. Ludwig said that Dr. Loren told him and his wife something he considered profound. “She said, ‘We don’t know how long it’s going to
`last. Enjoy every day,’ ” Mr. Ludwig recalled.
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`“That’s what we’ve done ever since.”
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`A version of this article appears in print on , Section D, Page 1 of the New York edition with the headline: An Immune System Trained to Kill Cancer
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`https://www.nytimes.com/2011/09/13/health/13gene.html
`
`5/5
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`UPenn Ex. 2002
`Miltenyi v. UPenn
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