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Thursday 27 June 2019
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What are the neurological side effects of CAR T-cell therapy?

The recent advent of chimeric antigen receptor (CAR) T-cell therapy has revolutionised the clinical treatment of cancer. Under the umbrella of immunotherapy, CAR T-cell treatment trains and strengthens a patient's own immune system to attack tumors. Early successes in clinical trials have led to approval of the treatment for recurrent blood cancers, including leukaemia and lymphoma.
 
Despite the therapeutic successes of CAR T-cell therapy, the intervention carries the risk of severe side effects. These include neurotoxicity, which can result in headache, confusion, and delirium, among other neural changes. These debilitating effects remain poorly understood and characterised. A team at Brigham and Women's Hospital in the US has catalogued the neurological symptoms of patients who had received CAR T-cell therapy to better understand its neurotoxic side effects. While neurological symptoms were prevalent - 77% of patients experienced at least one symptom -  they were also temporary. The findings are published in Brain.1
 
"The mechanism underlying CAR T-cell-associated neurotoxicity is unknown and symptoms can be very hard to predict," said lead author Daniel Rubin, MD, PhD, of the Department of Neurology at the Brigham. "We conducted this study to better define the specific neurologic symptoms experienced by patients after CAR T-cell therapy."
 
To define clinical symptoms of CAR-T-associated neurotoxicity, the team conducted an observational cohort study of 100 lymphoma patients admitted to the Dana-Farber/Brigham and Women's Cancer Center for CAR T-cell therapy between 2015 and 2018. The team evaluated symptoms from the start of CAR T-cell therapy infusion through two months' post-infusion. In addition, all diagnostic assessments, including laboratory tests and imaging scans, were reviewed.
 
"We shared a few clinical cases early in the therapies which were very severe and unusual from a neurological standpoint," said senior author Henrikas Vaitkevicius, MD, of the Department of Neurology. "This sparked an interest to collaborate with oncology and T-cell therapy groups, and allowed us to evaluate the majority of patients prospectively rather than retrospectively."
 
Their findings reveal the widespread prevalence of neurological symptoms after starting CAR-T therapy. The most prevalent symptom was encephalopathy, a type of brain disease that causes confusion, but additional symptoms such as headache, tremor, weakness and language dysfunction were also observed. Importantly, most of these effects were reversible, and symptoms almost always resolved over time.
 
In addition, the researchers observed a unique pattern of activity, or inactivity, in their study. The neurological deficits associated with therapy often originated from areas which appeared metabolically silent. This finding carries important implications for the clinical assessment of neurotoxicity and the use of imaging.
 
Reference
  1. Rubin DB et al. Neurological toxicities associated with chimeric antigen receptor T-cell therapy. Brain 2019;142(5):1334 DOI: 10.1093/brain/awz053

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