Worries, confusion after cancer trial deaths.

9 DECEMBER 2016 • VOL 354 ISSUE 6317 1211 SCIENCE sciencemag.org P H O T O : S T E V E G S C H M E IS S N E R / S C IE N C E P H O T O L IB R A R Y A n experimental cancer therapy is facing its biggest setback yet, after an unexpected complication killed seven people over about a year, five of them in a single clinical trial. The company, Seattle, Washington–based Juno Therapeutics, has its most troubled trial on hold and is racing to figure out why patients suffered fatal brain swelling. Researchers elsewhere are grappling with possible ramifications for the breakthrough treatment, which goes up for drug approval next year. “Why would we see this now? We don’t know, period,” says Stephan Grupp, a pediatric oncologist at the Children’s Hospital of Philadelphia in Pennsylvania. In several trials, he has treated more than 100 children with the experimental approach, in which a patient’s own immune cells are genetically engineered to fight cancer. None experienced the fluid buildup, known as cerebral edema, that killed adults in Juno’s trials. Grupp and others speculate that the explanation may lie in the specific product tested and the patient population, rather than in the overall strategy itself. Still, they are mostly in the dark. Cerebral edema “wasn’t on anybody’s radar,” Grupp admits. Company officials declined to comment, saying only that they are investigating. Several hundred people with advanced blood cancers, from toddlers to senior citizens, have received the treatment, called chimeric antigen receptor (CAR)-T cell therapy, with remarkable results (Science, 28 June 2013, p. 1514). Many have now been cancer free for years, and the therapy is part of a new arsenal of immune-based cancer therapies (Science, 20 December 2013, p. 1432). Doctors are beginning to test CAR-T therapy in solid tumors like lung cancer. Results there are mixed (Science, 2 September, p. 983). Like other cancer immunotherapies, CART therapy can overstimulate the immune system, triggering an out-of-control proliferation of immune cells that can shut down vital organs. The first child treated with CAR-T therapy, a 6-year-old girl with leukemia, 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