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Deaths in CAR-T Trials Haunt Promising New Cancer Treatment

Companies are racing to develop a new type of cancer therapy, but scientists are still assessing its safety.
December 1, 2016
Hans Bishop is the CEO of Seattle-based Juno Therapeutics, which last week reported two more patient deaths in a clinical trial testing a novel cancer therapy.

The deaths last month of two patients in a clinical trial testing a promising new type of cancer treatment are raising questions about the fate of therapies that use a patient’s own immune cells to fight off the disease.    

Juno Therapeutics, the Seattle company conducting the trial, announced it was halting its human tests of an experimental cancer therapy just before Thanksgiving after two patients with acute lymphoblastic leukemia died. Earlier this year, three patients died in the same clinical trial. But other investigators developing similar products are forging on with testing the new class of therapies, which have shown incredible promise for some patients with lethal cancers.

Dubbed CAR-T therapy, scientists take T cells from a patient and then genetically engineer them outside the body to recognize and attack cancer cells. The T cells are then infused back into the patient. If approved by the U.S. Food and Drug Administration, these therapies could be life-saving for patients with cancers that don’t respond to currently available treatments. 

Kite Pharma, which is the farthest along with its CAR-T therapy for non-Hodgkin's lymphoma, acknowledged last year that a patient died during its testing, but said the death was found to be unrelated to the treatment. Meanwhile, Novartis is moving forward with studying a CAR-T therapy for patients with certain types of lymphoma. Though these therapies represent the cutting-edge of cancer research, they’re known to have toxic side effects—and other patients have died in T-cell trials at the National Cancer Institute and University of Pennsylvania.

Despite the recent deaths, there is ample evidence that the approach can be effective. “The thing about everyone’s CAR-T cell products is that they work, and they work very well,” says Ronald Dudek, founder and president of Living Pharma, an early-stage CAR-T company. Dudek previously served as Juno’s vice president of commercial strategy from November 2013 to October 2014.

The problem is these engineered T cells have the potential to stimulate the immune system too much. This can lead to cytokine release syndrome, one of the well-known side effects of immune therapies like CAR-T. But the five patients in the Juno trial died from a different condition, cerebral edema, or swelling of the brain. In other trials of CAR-T therapies, neurological side effects have occurred but were mostly short-lived.

Terry Fry, a pediatric cancer doctor at the National Cancer Institute who is developing a CAR-T therapy, says CAR-T therapies are potentially “game-changing” for patients with poor odds of beating their cancers. But scientists don’t fully understand how they work or why some patients have serious side effects like neurotoxicity, he says. While some patients appear to be in complete remission after CAR-T treatment, Fry says, the recent deaths in the Juno trial should give researchers pause. 

“Most of these patients have no other therapeutic options, but that doesn’t mean that the toxicity is acceptable,” he says.

David Chang, chief medical officer and executive vice president of research and development at Kite Pharma, says deaths in CAR-T trials are likely caused by multiple factors rather than “one smoking gun.” The adult patients in the Juno trial had an aggressive type of cancer. “Because of their advanced stage of disease, they are more susceptible to adverse events,” he says.

Manufacturing conditions at facilities making these therapies can also alter the condition of the T cells when they’re put back into the patient, Chang says.

Dudek says he wouldn’t be surprised if the additional deaths in the Juno trial prompt some to lobby the FDA to mandate new safety measures for CAR-T therapies. For example, Texas-based Bellicum Pharmaceuticals is developing some CAR-Ts to have molecular “off” switches activated by a pill that could be taken if a patient reacts badly to the treatment.

On a conference call with investors last week, Juno CEO Hans Bishop said the company is still aiming to launch its first CAR-T therapy in 2018, despite the latest deaths. What’s unclear is whether Juno will completely scratch the problematic trial and focus on its other investigational CAR-T therapies instead. Juno is also developing CAR-Ts for lymphoma and other blood cancers.

Many experts agree that the FDA needs to collect more data on these therapies before approving one for patients, and earlier this year the agency proposed creating a database to monitor CAR-T safety that researchers could access. Though when contacted last week, a spokesperson for the FDA told MIT Technology Review that database was still in the planning stages.

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