Author: Laurel Hamers / Source: Science News

This wasn’t 15-year-old Connor McMahon’s first time in the hospital.
But the 107° fever he’d been running for three days had his dad frightened. The teen was hallucinating, talking gibberish and spouting curses.“I thought he was going to die,” says Connor’s father, Don McMahon, who stayed close as his son received and recovered from an experimental treatment for leukemia. “It was really hard to watch.” But the fever finally broke, and Connor returned home. Just a month later, in November 2016, he was cancer-free and back on the ice in his hockey skates and pads.
That episode was Connor’s third bout with acute lymphoblastic leukemia. The experimental treatment was a last hope for the boy, who was first diagnosed at age 3. He has spent a total of six years of his life receiving chemotherapy. When the cancer came back in 2016, the doctors said the prognosis wasn’t good.
At that point, “it was about quality of life, not quantity,” McMahon says. But when he and his wife, Michelle, learned about the experimental treatment, called CAR-T cell therapy, the family decided it wasn’t time to give up yet.

McMahon enrolled Connor in a clinical trial for a CAR-T cell therapy at Duke University Children’s Hospital, five hours from the family’s Atlanta home. Days later, doctors extracted immune cells called T cells from Connor’s blood and shipped them off to a lab in New Jersey. There, the cells were genetically modified to target and kill the cancer cells coursing through Connor’s bloodstream.
A month later, doctors injected those modified T cells into the teen’s body, where they multiplied. Over the next few weeks, that five-minute T cell infusion racked Connor’s body but also knocked the levels of cancer cells in his bloodstream down to zero.
CAR-T cell therapy has captivated cancer researchers and patients alike because of stories like Connor’s. The U.S. Food and Drug Administration approved two versions in late 2017. In clinical trials, the treatment that Connor took, called Kymriah, wiped away all signs of acute lymphoblastic leukemia in 52 of 68 children and young adults. Of those, 75 percent were still cancer-free six months later. And in a study of 101 patients taking Yescarta, a CAR-T therapy for adults with certain types of lymphoma, 51 percent of patients showed no sign of cancer after treatment. (In May, the FDA also approved Kymriah for people with certain lymphomas.) These results were particularly exciting because the patients in these trials were dealing with a recurrence of cancer or had been through at least two other treatments that didn’t work.
But these new therapies can come with scary side effects. A majority of patients who receive CAR-T cell therapy react like Connor did, with varying degrees of severity. Those same T cells that are outfitted to attack the cancer can send the immune system into overdrive by instigating a surge of proteins called cytokines into the bloodstream, triggering inflammation. Cytokine release syndrome, as it’s called, can cause high fevers, make patients’ hearts race out of control and send blood pressure plummeting. The cytokines can also attack the brain, causing seizures.
In a large, multihospital study of Kymriah, 54 of 68 patients experienced some form of cytokine release syndrome. Symptoms were severe enough in 32 patients to require intensive care hospitalization. Neurological problems are a risk as well. In 2016, five patients died from fatal brain swelling in a CAR-T cell clinical trial run by Seattle-based Juno Therapeutics. The company stopped the trial, and the deaths intensified questions about the treatment’s safety.
CAR-T cell therapy can cause severe side effects in cancer patients. Doctors need to be vigilant to manage those problems in the clinic.
Cytokine release syndrome | How is it managed? |
---|---|
High fever | An interleukin-6 inhibitor plus supportive care |
Low blood pressure | |
Delirium | |
Fatigue | |
Other side effects | How is it managed? |
Brain swelling | Corticosteroids, for severe cases |
Neurotoxicity | |
Seizures | |
Reduced numbers of healthy immune cels | Long-term immunoglobulin |
These side effects are one reason why both therapies are approved for only a narrow range of patients: people with a few very select kinds of blood cancers — certain types of leukemia and lymphoma — and only those whose cancer hasn’t responded to conventional treatments. And CAR-T therapy is offered only at select cancer treatment centers with trained teams that follow rigorous safety protocols to control side effects. Yescarta, for example, is available at just over 50 U.S. hospitals.
Many oncologists are convinced, however, that someday CAR-T cells could be used on a much wider group of patients and for a broader spectrum of cancers. Researchers are designing new forms of the treatment, changing the way that patients’ T cells are engineered to make the therapy less risky. Scientists are installing safety switches that can turn off CAR-T cells on command and designing T cells that activate only under certain conditions. Others are adding features that help the T cells more specifically target cancer cells but ignore healthy cells, or reduce collateral damage from T cell–boosting drugs. Meanwhile, doctors are learning how to better manage the side effects for patients.
“I think this is an incredibly exciting time,” says David Maloney, a physician and CAR-T cell researcher at the Fred Hutchinson Cancer Research Center in Seattle. The CAR-T cell technology is rapidly improving, and “our job is to do this safely and make it even more effective.”
Building a better T cell
Some immune system cells recognize cancer cells as abnormal and kill them, but sometimes that’s not enough. Researchers have tried for decades to harness the immune system to fight cancer more effectively. Doctors have used vaccines or given patients lab-made versions of immune system proteins to heighten patients’ immune responses.
“Immunotherapy goes back a long time, but successful immunotherapy is just in its infancy,” says Paul Martin, a pediatric oncologist at Duke University who treated Connor with CAR-T cells. He says CAR-T therapy is part of a new, more promising wave of immune therapies against cancer.
Each batch of CAR-T cell therapy is created for a specific patient. First, T cells are removed from the patient.




The CAR, or chimeric antigen receptor, has parts on the outside (red) of the T cell that help it recognize the cancer cell and components on the inside (dark blue and gold) that help it communicate with and attack cancer cells.

The underpinnings of CAR-T cell therapy were developed in research labs in the 1990s, and the first CAR-T cells fought off cancers in mice in the early 2000s. But with last year’s FDA approvals for the two CAR-T cell therapies, interest has exploded (SN: 12/23/17, p. 29). As of June 14, the government’s registry of clinical studies, ClinicalTrials.gov, included 272 active studies for CAR-T cell therapies, mostly in the United States, China and Europe. Hundreds more variations are being designed and tinkered with in research labs around the world.
CAR-T cell therapy works by taking advantage of cells’ natural communication systems. The surface of every cell is studded with proteins that send messages between cells…
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