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NEWS CANCER IMMUNOTHERAPY Worries, confusion after cancer trial deaths edema is essentially an extreme version of the brain issues doctors were already ren experimental cancer therapy is faccording or is something else. Either way, ing its biggest setback yet, after an the cause could lie in one or several specific unexpected complication killed seven features of the Juno trial. For one, most of people over about a year, five of them the deaths are in adults with acute leukemia; in a single clinical trial. The company, people with this disease tend to have more Seattle, Washington–based Juno Therside effects from CAR-T therapy, in part beapeutics, has its most troubled trial on hold cause the T cells can expand more quickly and is racing to figure out why patients suffor reasons that are not well understood. fered fatal brain swelling. Researchers elseThis increases effectiveness but also risks. where are grappling with possible Other variables include the age of ramifications for the breakthrough trial participants—children often treatment, which goes up for drug have fewer side effects—and the approval next year. chemotherapy given before the “Why would we see this now? T cells. We don’t know, period,” says Finally, there’s the design of the Stephan Grupp, a pediatric oncoCAR-T cells themselves. All incorlogist at the Children’s Hospital porate a “costimulatory molecule” of Philadelphia in Pennsylvania. that encourages proliferation. The In several trials, he has treated five deaths occurred in Juno’s trial more than 100 children with that uses a molecule called CD28. the experimental approach, in The company’s other trial, with which a patient’s own immune two edema deaths, relies on a difcells are genetically engineered ferent molecule, called 4-1BB. Noto fight cancer. None experivartis, which is also running trials enced the fluid buildup, known in acute leukemia and has not reas cerebral edema, that killed ported cerebral edema, relies on adults in Juno’s trials. Grupp 4-1BB, too. and others speculate that the exA third company, Kite Pharma, planation may lie in the specific based in Santa Monica, Califorproduct tested and the patient nia, is using CD28 but is treating population, rather than in the adults with advanced lymphoma, overall strategy itself. Still, they not leukemia; it hasn’t seen any are mostly in the dark. Cerebral A new cancer treatment genetically engineers T cells (blue) to attack malignant cases of cerebral edema, execuedema “wasn’t on anybody’s racells like this lymphocyte cell (orange). tives say. Kite and Novartis plan to dar,” Grupp admits. Company apply for FDA approval next year. officials declined to comment, saying only ago, but it didn’t trigger alarm bells. Then Better animal models could help solve that they are investigating. in July, the company revealed a cluster of the mystery. The most popular CAR-T therSeveral hundred people with advanced three more deaths in a different trial, for apy model, in mice, failed to predict any blood cancers, from toddlers to senior citiacute leukemia. Juno suggested these were neurotoxicity. Earlier this week, a team at zens, have received the treatment, called chidue to a chemotherapy drug called fludathe Seattle Children’s Research Institute in meric antigen receptor (CAR)-T cell therapy, rabine that the patients also received. Juno Washington reported at the ASH meeting with remarkable results (Science, 28 June eliminated fludarabine from its protocol, that they had tested a CAR-T therapy in 2013, p. 1514). Many have now been cancer and the U.S. Food and Drug Administrarhesus monkeys, and that the animals defree for years, and the therapy is part of a new tion (FDA) allowed the trial to resume. veloped abnormal behaviors and tremors, arsenal of immune-based cancer therapies But late last month, edema killed two suggesting neurologic effects. (Science, 20 December 2013, p. 1432). Doctors more patients in the same trial, which is “It’s clearly sobering,” Mackall says of the are beginning to test CAR-T therapy in solid now back on hold. Neither the company nor Juno deaths. “I’ve lived, eaten, and breathed” tumors like lung cancer. Results there are FDA has released much information since, this therapy, and “you think you understand mixed (Science, 2 September, p. 983). including the total number of patients it.” Still, she points out, all cancer drugs come Like other cancer immunotherapies, CARtreated. Last weekend at the annual Ameriwith huge risks, and that’s something paT therapy can overstimulate the immune can Society of Hematology (ASH) meeting, tients, their doctors, and drug regulators gensystem, triggering an out-of-control prolifhowever, Juno reported that a seventh paerally accept given the severity of the disease. eration of immune cells that can shut down tient, with chronic leukemia, had also died “Let’s get rid of the hype here: This is a new vital organs. The first child treated with from cerebral edema. therapy that is very promising,” Mackall says, CAR-T therapy, a 6-year-old girl with leukeMackall and others wonder whether the “but we still have a lot to learn about it.” j By Jennifer Couzin-Frankel PHOTO: STEVE GSCHMEISSNER/SCIENCE PHOTO LIBRARY A mia, nearly died from this. “The community recognized this as a huge threat to our patients and to the therapy” and found drugs to manage it, says Crystal Mackall, who heads the cancer immunology and immunotherapy program at Stanford University in Palo Alto, California. The therapy was also known to carry neurological risks, including confusion, delirium, seizures, and even a temporary inability to speak. But they have not been fatal. Juno reported the first death about a year SCIENCE sciencemag.org 9 DECEMBER 2016 • VOL 354 ISSUE 6317 Published by AAAS 1211 Downloaded from http://science.sciencemag.org/ on January 9, 2017 Experimental immune treatment linked to fatal brain swelling Worries, confusion after cancer trial deaths Jennifer Couzin-Frankel (December 8, 2016) Science 354 (6317), 1211. [doi: 10.1126/science.354.6317.1211] This copy is for your personal, non-commercial use only. Article Tools Permissions Visit the online version of this article to access the personalization and article tools: http://science.sciencemag.org/content/354/6317/1211 Obtain information about reproducing this article: http://www.sciencemag.org/about/permissions.dtl Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2016 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS. Downloaded from http://science.sciencemag.org/ on January 9, 2017 Editor's Summary