Elevated Blood Levels of Neurofilament Light Chain Predict Likelihood of Neurotoxicity Following CAR-T Immunotherapy

An elevated level of neurofilament light chain (NfL) in the blood plasma can identify which patients are likely to develop neurotoxic side effects in the days and weeks following CAR-T cell therapy.

Cell-based immunotherapy (CAR-T cell therapy) has revolutionized the treatment of certain types of leukemia and lymphoma. This method is based on chimeric antigen receptor T-cells (also known as CAR-T cells) that have been genetically engineered to produce an artificial T-cell receptor for use in immunotherapy. The receptors are chimeric because they combine both antigen-binding and T-cell activating functions into a single receptor. The premise of CAR-T immunotherapy is to modify T-cells to recognize cancer cells in order to more effectively target and destroy them. In practice, T-cells are harvested, genetically altered, and then infused as CAR-T cells into patients to attack their tumors.

Image: A simple blood test - administered before CAR-T cell treatment is initiated - may identify which patients are predisposed to developing neurotoxic side effects after CAR-T cell therapy. Severe side effects can include seizures, brain swelling, and strokes. Evidence of a stroke (red arrows) is seen on this MRI scan of the brain of a patient who developed neurotoxic side effects after CAR-T cell therapy (Photo courtesy of Dr. Omar Butt, Washington University School of Medicine)

CAR-T cells can be derived either from T-cells in a patient's own blood (autologous) or derived from the T-cells of another healthy donor (allogeneic). Once isolated, these T-cells are genetically engineered to express a specific CAR, which programs them to target an antigen that is present on the surface of tumors. For safety, CAR-T cells are engineered to be specific to an antigen expressed on a tumor that is not expressed on healthy cells.

Neurological toxicity, known as immune effector cell–associated neurotoxicity syndrome (ICANS), is often associated with CAR-T cell treatment. The underlying mechanism is poorly understood. Clinical manifestations include delirium, the partial loss of the ability to speak coherently while still having the ability to interpret language (expressive aphasia), lowered alertness (obtundation), and seizures. During some clinical trials, deaths caused by neurotoxicity have occurred with the main cause of death being cerebral edema.

Recently, neurofilament light chain (NfL), an axonal structural protein with elevated levels in multiple neurodegenerative and neuroinflammatory diseases, has emerged as a potential biomarker for ICANS. It is a biomarker that can be measured with immunoassays in samples of cerebrospinal fluid or plasma and reflects axonal damage in a wide variety of neurological disorders. It is a useful marker for disease monitoring in amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, and more recently Huntington's disease.

Investigators at Washington University School of Medicine (St. Louis, MO, USA) examined the relationship between NfL and ICANS in order to determine whether levels of NfL prior to commencing CAR-T cell therapy could permit early screening and identification of patients most at risk for development of ICANS.

For this study, the investigators examined plasma NfL levels in 30 patients with detailed medical and treatment history, including all major pre-treatment and post-treatment risk factors. Patients’ NfL levels were measured at seven time points: baseline (pre-lymphodepletion), during lymphodepletion, and one, three, seven, 14, and 30 days post-infusion. Various statistical models were used to determine the association between NfL levels, ICANS, and potential risk factors including demographic (age, sex), oncologic (tumor burden, history of CNS involvement), neurologic (history of nononcologic CNS disease or neuropathy), and neurotoxic exposure histories (vincristine, cytarabine, methotrexate, or CNS radiotherapy).

Results revealed that individuals who developed ICANS had elevations in NfL prior to lymphodepletion and CAR-T cell infusion compared with those who did not develop ICANS. Baseline NfL levels further predicted ICANS development with high accuracy and specificity. Levels of NfL remained elevated across all time points, up to 30 days post-infusion. Baseline NfL levels correlated with ICANS severity but not demographic factors, oncologic history, nononcologic neurologic history, or history of exposure to neurotoxic therapies.

“Our study suggests that some patients receiving CAR-T cell therapy have previously undetected damage to neurons present at baseline, before we even begin preparing them for this treatment,” said first author Dr. Omar H. Butt, instructor in medicine at Washington University School of Medicine. “We do not know the origin of this damage, but it appears to predispose them to developing neurotoxic complications. If we understand who is at risk of these complications, we can take early steps to prevent it or reduce the severity. We are just seeing the tip of the iceberg in terms of the actual disease process, and that is where many of our future studies are going. We are trying to get a better sense of what is causing these changes to begin with. And in later stages, even after symptoms have resolved, we still see these elevated NfL levels.”

The study was published in the September 1, 2022, online edition of the journal JAMA Oncology.

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