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None of the 25 patients with refractory B cell lymphoma who received a modified anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in a phase 1 trial experienced serious neurological toxicity or cytokine-release syndrome, researchers recently reported in Nature Medicine.
These life-threatening adverse effects are difficult and costly to manage and represent the biggest barrier to clinical use of CAR T-cell therapy, according to the study’s senior author, Si-Yi Chen, MD, PhD, of the University of Southern California Keck School of Medicine. The neurological toxicities associated with approved CAR T-cell therapies include encephalopathy, seizures, and altered consciousness, while cytokine-release syndrome is marked by severe flu-like symptoms, shortness of breath, low blood pressure, and fast heart rate.
Chen’s team genetically modified the anti-CD19 CAR molecule used in tisagenlecleucel, the acute lymphoblastic leukemia CAR T-cell therapy marketed as Kymriah. Their new molecule, CD19-BBz(86), allowed T cells to bind and kill cancer cells, while producing cytokines at much lower levels and proliferating at slower rates than its predecessor. In the trial, 6 of 11 patients achieved complete remission after receiving the highest dose, with ongoing clinical responses in 5 of the 6. The median duration of response in these patients was more than 181 days, and no participants in the trial required medications to manage adverse effects.
“The reduced cytokine production and proliferation of the modified CAR T cells may allow the patient’s body to clear the cytokines before they build up to the toxic levels in the bloodstream,” Chen said, adding that a larger multicenter trial is still needed.
Safer CAR T-cell therapy could lower treatment costs and dramatically broaden access beyond major cancer centers. “Hopefully, it could someday be administered in outpatient settings,” Chen said.
Abbasi J. Safer CAR T-Cell Therapy. JAMA. 2019;321(22):2155. doi:10.1001/jama.2019.7551
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