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Insight into neurotoxic side effects of CAR T cell therapy



The recent advent of chimeric antigen receptor (CAR) T cell therapy has revolutionized clinical cancer treatment. Under the umbrella of immunotherapy, CAR T-cell treatment trains and improves a patient's immune system to attack tumors. Early successes in clinical trials have led to approval of the treatment of recurrent blood cancers, including leukemia and lymphoma.

Despite the therapeutic successes of CAR T cell therapy, the intervention has the risk of serious side effects. These include neurotoxicity, which can result in headache, confusion and delirium, in addition to other neural changes. These debilitating effects remain poorly understood and characterized. A team from Brigham and Women & # 39; s Hospital recently cataloged the neurological symptoms of patients who had received CAR T cell therapy to better understand their neurotoxic side effects. Although neurological symptoms were common – 77 percent of patients experienced at least one symptom – they were also temporary. The findings are published in Brain.

The mechanism underlying CAR T cell associated neurotoxicity is unknown and the symptoms may be difficult to predict. We conducted this study to better define the specific neurological symptoms of patients after CAR T cell therapy. "

Daniel Rubin, MD, PhD, Department of Neurology at Brigham, lead author

To define clinical symptoms of CAR-T associated neurotoxicity, the team conducted an observational cohort study of 100 lymphoma patients included in Dana-Farber / Brigham and Women & # 39; s Cancer Center for CAR T cell therapy between 2015 and 2018. The team evaluated the symptoms from the start of CAR T cell therapy infusion until two months after the infusion. In addition, all diagnostic assessments, including laboratory tests and imaging scans, were assessed.

"We shared a few clinical cases early in therapies that were very serious and unusual from a neurological point of view," said senior author Henrikas Vaitkevicius, MD, of the Neurology Department. "This sparked the interest to collaborate with oncology and T-cell groups and enabled us to prospectively evaluate the majority of patients rather than afterwards."

Their findings demonstrate the widespread prevalence of neurological symptoms after starting CAR-T therapy. The most common symptom was encephalopathy, a type of brain disease that causes confusion, but additional symptoms such as headache, trembling, weakness, and language disorders were also observed. Importantly, most of these effects were reversible and the symptoms almost always disappeared over time.

In addition, the researchers observed a unique pattern of activity, or inactivity, in their studies. The neurological deficits associated with therapy often come from areas that appear to be metabolically silent. This finding has important implications for the clinical assessment of neurotoxicity and the use of imaging.

Despite the frequent occurrence of neurological symptoms, imaging studies such as MRI, which serve as a cornerstone of neurological diagnosis, were almost always normal. In contrast, diagnostic studies that more directly evaluated neuronal functioning, such as EEG and PET scans, were able to reliably detect and predict neurological dysfunction. "

Daniel Rubin

As a next step, researchers build and validate a model for more accurate scoring and diagnosis of CAR T-associated neurotoxicity.

Source:

Brigham and the women's hospital

Reference of the magazine:

Rubin, D.B. et al. (2019) Neurological toxicity associated with chimeric antigen receptor T cell therapy. Brain. doi.org/10.1093/brain/awz053


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