Language dysfunction-associated EEG findings in patients with CAR-T related neurotoxicity

Abstract

Chimeric antigen receptor-modified T cells (CAR-T) have emerged as a promising immunotherapeutic approach in relapsed/refractory haematolgical malignancies. Broader application is limited by unique toxicities, notably, neurotoxicity (NTX). Language dysfunction is among the most frequent symptoms of NTX, the underlying mechanisms of which remain to be elucidated. Electroencephalogram (EEG) is an important tool to monitor for NTX and may provide insights into language dysfunction.AimWe aimed to characterise language dysfunction and define electroencephalographic signatures after CAR-T cell therapy.MethodsWe reviewed the clinical presentation and EEG findings of 20 adult patients presenting with language dysfunction after CAR-T cell infusion. The cohort included a subset of patients treated with investigational CD19-directed CAR-T cells for non-Hodgkin’s lymphoma (n=17), acute lymphoblastic leukaemia (n=1), follicular lymphoma (n=1) and chronic lymphocytic leukaemia (n=1).ResultsLanguage dysfunction presented within 14 days of CAR-T cell infusion in 16 (84%) patients. Ten (50%) patients had mild word-finding difficulties and 10 (50%) had marked dysphasia with profound word-finding difficulties; the latter were all associated with generalised rhythmic delta activity or generalised periodic discharges on EEG.ConclusionsLanguage dysfunction after CAR-T cell therapy is associated with generalised EEG abnormalities.

Continuous EEG monitoring detects nonconvulsive seizure and Ictal-Interictal Continuum abnormalities in moderate to severe ICANS following systemic CAR-T therapy

“…Notably no patients in our cohort had evidence of focal seizures, and very few had focal slowing or lateralized discharges on EEG despite EEG monitoring in 12 of 13 patients with language deficits on neurological examination. This is in line with a study of 20 patients with expressive language deficits noting predominantly generalized EEG abnormalities in ICANS patients with language dysfunction, 25 but in contrast to a recent cohort associating language abnormalities with focal EEG abnormalities. 15 While our sample size is small, this discrepancy is of note as the majority of our patients had long duration cEEG monitoring making the possibility of identifying focal slowing or periodic discharges more likely.…”

In vivo dynamics and anti-tumor effects of EpCAM-directed CAR T-cells against brain metastases from lung cancer

“…However, the fact that locally injected CAR T-cells did not migrate into the systemic circulation may also be beneficial in reducing CAR T-cell-mediated side effects. Such toxicities most frequently include neurologic symptoms such as seizures, 32 , 33 a sepsis-like phenotype entitled ‘cytokine release syndrome,’ 33 , 34 hematological effects, 35 and even fatalities have been reported. 36 Given the expression of EpCAM as a pan-epithelial cell marker on healthy alveolar tissue, 37 on-target/off-tumor effects due to shared expression of target antigens on neoplastic and healthy tissue might be particularly problematic in EpCAM-directed CAR T-cells.…”

Site-Specific Considerations on Engineered T Cells for Malignant Gliomas

“…Trials on other cancer entities unveiled some side effects which were associated with the systemic i.v. administration of CAR-T cells including the immune effector cell–associated neurotoxicity syndrome (ICANS), cytokine release syndrome (CRS) and on-target-off-tumor toxicities [ 55 , 56 ]. It still not clear whether alternative local delivery routes would evade, develop, or enhance such side effects.…”