7/12/22, 3:37 PM
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`A Cancer Treatment Makes Leukemia Vanish, but Creates More Mysteries - The New York Times
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`https://www.nytimes.com/2022/02/02/health/leukemia-car-t-immunotherapy.html
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`A Cancer Treatment Makes Leukemia Vanish, but Creates More Mysteries
`Two early recipients of CAR T immunotherapy were free of a blood cancer nearly a decade after receiving the therapy.
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`By Gina Kolata
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`Feb. 2, 2022
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`Doug Olson was feeling kind of tired in 1996. When a doctor examined him she frowned. “I don’t like the feel of those lymph nodes,” she
`said, poking his neck. She ordered a biopsy. The result was terrifying. He had chronic lymphocytic leukemia, a blood cancer that mostly
`strikes older people and accounts for about a quarter of new cases of leukemia.
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`“Oh Lordy,” Mr. Olson said. “I thought I was done for.” He was only 49 and, he said, had always been healthy.
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`Six years went by without the cancer progressing. Then it started to grow. He had four rounds of chemotherapy but the cancer kept
`coming back. He had reached pretty much the end of the line when his oncologist, Dr. David Porter at the University of Pennsylvania,
`offered him a chance to be among the very first patients to try something unprecedented, known as CAR T cell therapy.
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`In 2010, he became the second of three patients to get the new treatment.
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`At the time, the idea for this sort of therapy “was way out there,” said Dr. Carl June, the principal investigator for the trial at Penn, and he
`had tempered his own expectations that the cells he was providing to Mr. Olson as therapy would survive.
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`“We thought they would be gone in a month or two,” Dr. June said.
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`Now, a decade later, he reports that his expectations were completely confounded. In a paper published Wednesday in Nature, Dr. June
`and his colleagues, Dr. J. Joseph Melenhorst and Dr. Porter, report that the CAR T treatment made the cancer vanish in two out of the
`three patients in that early trial. All had chronic lymphocytic leukemia. The big surprise, though, was that even though the cancer seemed
`to be long gone, the CAR T cells remained in the patients’ bloodstreams, circulating as sentinels.
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`“Now we can finally say the word ‘cure’ with CAR T cells,” Dr. June said.
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`Although most patients will not do as well, the results hold out hope that, for some, their cancer will be vanquished.
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`But mysteries remain.
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`The treatment involves removing T cells, white blood cells that fight viruses, from a patient’s blood and genetically engineering them to
`fight cancer. Then the modified cells are infused back into a patient’s circulation.
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`Doug Olson in Bend, Ore., in December. In 2010, he became one of three patients to
`undergo CAR T cell therapy as part of a clinical trial. Olson family photo
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`https://www.nytimes.com/2022/02/02/health/leukemia-car-t-immunotherapy.html
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`1/2
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`UPenn Ex. 2004
`Miltenyi v. UPenn
`IPR2022-00855
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`7/12/22, 3:37 PM
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`A Cancer Treatment Makes Leukemia Vanish, but Creates More Mysteries - The New York Times
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`In the case of chronic lymphocytic leukemia, the type Mr. Olson had, the cancer involved B cells, the antibody-forming cells of the immune
`system. A patient’s T cells are taught to recognize B cells and destroy them. The result, if the treatment succeeded, would be to destroy
`every B cell in the body. Patients would be left with no B cells. But also no cancer. They would require regular infusions of antibodies in the
`form of immunoglobulin infusions.
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`The therapy has helped many with blood cancers, and has proved particularly effective in patients with acute leukemias and other blood
`cancers. By contrast, those like Mr. Olson with chronic lymphocytic leukemia, also known as CLL, have seen less success. Among those
`with that cancer, about a third to a fifth go into remission with CAR T therapy, but many whose cancers disappear later relapse.
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`“The question is not only why some patients relapse or are resistant to therapy but why are some patients cured?” said Dr. John F.
`DiPersio, chief of the division of oncology at Washington University in St. Louis, who was not involved in the study.
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`The CAR T treatment has also caused serious side effects in some patients like high fevers, comas, dangerously low blood pressure and
`even death — although in most patients the alarming symptoms resolve. It has not yet worked in people with the solid tumors found in
`conditions like breast and prostate cancer.
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`Just as strange as the inability of CAR T to help most cancer patients is the fate of those modified T cells in the cured patients.
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`The genetic modification involved a subset of T cells known as CD8 cells, which are assumed to be the ones that actually kill the cancer.
`They are the assassins of the immune system.
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`But assassins need helpers and for the CD8 cells, the helpers are another group of T cells known as CD4 cells.
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`At first, the CD8 cells seemed to be acting exactly as was hoped in Dr. June’s study. The modified CD8 T cells almost immediately killed
`between 3 ½ and 7 pounds of cancer cells in the bodies of Mr. Olson and the first patient in the study, William Ludwig, who was also cured
`of his cancer but died last year from Covid-19.
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`After the CD8 cells did their job, they remained in the blood but, unexpectedly, they turned into CD4 cells. And when the Penn
`investigators removed CD4 cells from the blood of Mr. Ludwig and Mr. Olson, they saw that those cells could kill B cells in the laboratory.
`The CD4 cells had turned into assassins or, Dr. DiPersio noted, “at least guardians that can keep the tumor cells at bay and undetectable in
`the patient for years.”
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`Could the CD4 cells remain in the blood with no cancer cells to kill? Or were they there because the leukemia was not really gone but
`instead kept trying to return, only to be attacked by CD4 cells?
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`“We can’t find any leukemia cells in Doug,” Dr. June said. But, he added, perhaps they are still there in tiny quantities and emerging, only
`to be knocked back by CD4 cells, “like whack-a-mole,” he said.
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`He suspects, though, that the CD4 cells are more like guards.
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`“The leukemia is gone, but they stay on the job,” he said.
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`Whatever the mechanism, Dr. Porter said, the result “is beyond my wildest imagination.”
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`“Oncologists don’t use words like ‘cure’ lightly or easily or, frankly, very often,” he said. “I guarantee that it’s not being used lightly. The
`patients we treated had far advanced disease,” he noted, adding, “the biggest disappointment is that it doesn’t work all the time.”
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`“Historically, if these cancers don’t recur in two to five years the likelihood of relapse is low,” said Dr. Hagop M. Kantarjian, chairman of the
`department of leukemia at the University of Texas’s M.D. Anderson Cancer Center.
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`For Mr. Olson, now 75 and living in Pleasanton, Calif., life is good. He still shakes his head over the amazing coincidence that his oncologist
`just happened to be an investigator in that clinical trial a decade ago.
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`“I’m a lucky man,” he said.
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`Gina Kolata writes about science and medicine. She has twice been a Pulitzer Prize finalist and is the author of six books, including “Mercies in Disguise: A Story of Hope, a
`Family's Genetic Destiny, and The Science That Saved Them.” @ginakolata
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`•
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`A version of this article appears in print on , Section A, Page 17 of the New York edition with the headline: Potential Leukemia Cure Leads to New Mysteries
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`https://www.nytimes.com/2022/02/02/health/leukemia-car-t-immunotherapy.html
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`2/2
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`UPenn Ex. 2004
`Miltenyi v. UPenn
`IPR2022-00855
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