Averting toxic side effects from CAR-T cancer treatments

As excited as the oncology community is about the recent approval of Kymriah, Novartis’ CAR-T treatment for some patients with lymphoma, concerns about side effects remain. Some patients in clinical trials of Novartis’ product and others have developed a dangerous immune reaction called cytokine release syndrome, while others have suffered from neurotoxicity. The side effects can be life-threatening.

Now, scientists at Fred Hutchinson Cancer Research Center said they’ve identified biomarkers associated with cytokine release syndrome and neurotoxicity—and they’ve created algorithms that they believe can be used to predict when the effects are likely to be life-threatening. Their research was published in the journal Cancer Discovery.

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To identify the biomarkers, the research team closely tracked 133 patients participating in a trial of a CAR-T that was developed at Fred Hutch to treat chronic lymphocytic leukemia, non-Hodgkin lymphoma or acute lymphoblastic leukemia. They timed the onset of symptoms and the path to resolution, conducting detailed pathology testing and imaging along the way. Most of the patients developed cytokine release syndrome, which resolved on its own, but 10 suffered severe symptoms, according to a release.

One characteristic common in patients who suffered severe cytokine release or neurotoxicity was that the endothelial cells in the linings of their blood vessels became hyperactivated. That led the research team to conclude that testing for biomarkers of endothelial activation could help identify the CAR-T patients who face the highest risk of severe side effects.

The researchers identified two key criteria for predicting severe cytokine release syndrome: a fever of at least 102 and high levels of a particular immune cytokine called MCP-1. Patients who also had high levels of the cytokine IL-6 faced an increased risk of neurotoxicity, the researchers said. They believe cytokine release syndrome is the precursor for most cases of neurotoxicity, though more research would be needed to determine the link between the two, they said.

The study was partly funded by Juno Therapeutics, which fell to third place in the CAR-T race behind Novartis and Kite after a string of deaths last year in a trial for what was once its lead candidate, JCAR015. The deaths were attributed to severe swelling in the brain, or cerebral edema. Juno dropped the CAR-T from its pipeline in March of this year.

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The Fred Hutch research builds upon the ongoing work of researchers there to develop a safer CAR-T. Last December, at the American Society of Hematology (ASH) meeting, they announced positive results from an early trial of their CAR-T leukemia treatment, which is made by combining two different cell subsets. By creating distinct subsets of cells for each patient—and using biomarkers to predict cytokine release and neurotoxicity—they believe they’ll be able to improve the success rate of CAR-T while also reducing side effects.

Other Fred Hutch scientists are developing entirely new technologies to make CAR-T treatments safer. One team, for example, is using nanoparticles to remove a particular gene from T cells that normally causes them to attack healthy tissues. The same nanoparticles may be able to be used to enhance the production of T cells that kill cancerous targets—and that remember to attack the cancer should it ever reappear.

Cytokine release syndrome can be treated with steroids and immune modulating drugs, though there is no universally accepted protocol for using these drugs in CAR-T patients. The Fred Hutch researchers hope their latest study will inform efforts to develop treatment strategies and formally test them in clinical trials.