Cancer researchers study toxic side effects of new treatments


One of the most promising new cancer treatments involves altering patients’ own immune cells to attack blood cancers. But it comes with a big downside: It can cause serious side effects, including high fevers and sharp drops in blood pressure as well as potentially fatal brain swelling.

Now researchers at two major cancer centers - Fred Hutchinson Cancer Research Center in Seattle and MD Anderson Cancer Center in Houston - are homing in on these toxic complications to better understand why they occur, which patients are most vulnerable to the side effects and how to prevent them.

The new cancer treatment, called CAR T-cell therapy, involves extracting immune cells called T cells from the patient, genetically modifying them to attack the cancer, and returning them to the patient’s body. One such treatment has been approved for children and young adults with a certain kind of leukemia, and more are on the way for patients with treatment-resistant lymphomas and other blood cancers.

In two new papers, researchers at Fred Hutchinson provide detailed descriptions of the two most common side effects - cytokine release syndrome, or CRS, and neurotoxicity. The work was based on a clinical trial of 133 patients with leukemia or non-Hodgkin’s lymphoma that didn’t respond to standard therapies.

CRS, which can cause flulike symptoms, usually is mild, but 10 patients in the trial had severe cases. Neurotoxicity, which often is more dangerous, can cause delirium, brain swelling and difficulty finding words. As previously reported, complications of one or both of the side effects were fatal for a small number of patients.

The new cancer treatment has been “highly effective at getting these high-risk patients into remission,” said Cameron Turtle, a Fred Hutchinson immunotherapy expert who led the research into side effects. “But it’s essential that we understand the side effects.” He noted that the papers were based on the cancer center’s specific CAR T-cell product but said that different versions of the treatment from academia and industry have many common elements.

Turtle and his colleagues identified biomarkers, or physiological indicators, associated with the complications that might alert doctors to intervene. One of the new findings is that increased activity in the linings of blood vessels is linked to severe cases of both kinds of side effects.

In some patients who experienced extreme neurotoxicity, the scientists found, the blood-brain barrier, which protects the brain from potentially dangerous substances circulating in the blood, had broken down. And they concluded that patients who develop a high fever in the first 36 hours after treatment are at increased risk for severe neurotoxicity.

The researchers said the incidence of severe side effects has decreased as doctors have gained more experience in handling CAR T-cell therapy. The paper on neurotoxicity was published online Oct. 12 in Cancer Discovery; the one on cytokine release syndrome appeared online Sept. 18 in the journal Blood.

Meanwhile, researchers at MD Anderson Cancer Center, in an article in Nature Reviews Clinical Oncology last month, proposed guidelines for systematically dealing with the toxicities caused by the drugs.

That review was based on 100 patients treated at MD Anderson, Moffitt Cancer Center in Tampa, the Sylvester Cancer Center at the University of Miami and the Mayo Clinic Cancer Center in Rochester, Minn. The researchers developed a simple way to spot neurotoxicity: Ask patients to name the year and month, three nearby objects and the name of the president - and to count backward from 100 by tens.



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