Neurological updates: neurological complications of CAR-T therapy

Abstract

Chimeric antigen receptor (CAR)-expressing T cells now offer an effective treatment option for people with previously refractory B cell malignancies and are under development for a wide range of other tumours. However, neurological toxicity is a common complication of CAR-T cell therapy, seen in over 50% of recipients in some cohorts. Since 2018, the term immune effector cell-associated neurotoxicity syndrome (ICANS) has been used to describe and grade neurotoxicity seen after CAR-T cells and other similar therapies. ICANS following CAR-T therapy is usually self-limiting but can necessitate admission to the intensive care unit and is rarely fatal. As CAR-T therapies enter routine clinical practice, it is important for neurologists to be aware of the nature of neurological complications. Here, we summarise the clinical manifestations, mechanisms, investigations and recommended treatment of CAR-T-related neurotoxicity, focusing on the licensed CD19 products.

Frontal predominant encephalopathy with early paligraphia as a distinctive signature of CAR T-cell therapy-related neurotoxicity

“…In all cases, paligraphia was followed by a rapid neurological deterioration with frontal predominant encephalopathy that required transfer to ICU for three patients. In previous studies, neurotoxicity was observed with a mean onset of 5 days after infusion, even though it developed within 24 h since reinfusion in a subgroup of patients [ 7 , 11 ], as we observed in two cases, requiring early management. Despite the use of specific aggressive treatment, one of our cases died from CAR T-cell therapy-related toxicity, while another one because of CAR T-cell therapy failure (disease progression).…”

“…Clinical manifestations of ICANS are heterogeneous and may have a progressive or fluctuating course, ranging from mild cognitive slowing, headache and tremor, to language disorders, seizure, motor deficits and encephalopathy, potentially leading to akinetic mutism and death [ 2 , 3 ]. Steroids are currently the first-line therapy for ICANS, despite potential interference with CAR T-cell anti-tumour action [ 2 , 5 , 7 , 8 ]. Hence, it is paramount to identify early clinical and instrumental findings of neurotoxicity to detect early stages of ICANS, define the prognosis and guide the appropriate treatment.…”

Is the Frontal Lobe the Primary Target of SARS-CoV-2?

“…It has been suggested that COVID-19 patients could develop a form of cytokine-mediated neuroinflammatory encephalopathy, the immune effector cellassociated neurotoxicity syndrome (ICANS), due to the massive cytokine storm induced by COVID-19 systemic infection [13]. ICANS is a neuropsychiatric syndrome that may include frontal-type changes, such as confusion, short-term memory impairment, expressive deficits, and behavior disturbances including impulsivity, emotional lability, abulia, or akinetic mutism as clinical phenotype [13,21,22].…”

Challenges and Prospects for Designer T and NK Cells in Glioblastoma Immunotherapy

“…These include non-ubiquitous expression of the target antigen, physical barriers such as the blood–brain barrier (BBB) and extracellular matrix, immunosuppressive cells and cytokines, which are all present within a hostile, often hypoxic tumour microenvironment [ 34 ]. These obstacles are compounded by antigen loss [ 69 ] and serious adverse events observed in CAR T clinical trials, such as immune effector cell-associated neurotoxicity syndrome (ICANS) [ 70 ] and cytokine release syndrome (CRS) [ 71 ] in a brain encapsulated in an unyielding, bony cranium.…”