2023 Post-doctoral Clinical Fellowship
Longitudinal Neurocognitive Phenotyping of Chimeric Antigen Receptor (CAR) T-Cell Neurotoxicity
Chimeric antigen receptor (CAR) T-cell therapy has revolutionised treatment of B cell malignancies but is associated with significant neurotoxicity. 21-64% of recipients experience immune effector cell-associated neurotoxicity syndrome (ICANS), typically around day five. ICANS is a poorly understood encephalopathy with relatively distinct features: patients have aphasia and abulia but are otherwise awake and alert. However, the exact nature of cognitive deficits in ICANS and how these might evolve over time has not been characterised. It is therefore not known if early subtle deficits might precede and predict the development of ICANS. It is also unclear whether any pre-existing cognitive deficits increase the risk of developing ICANS, or if there are any persistent long-term deficits. Treatment of ICANS is currently with steroids but these attenuate the efficacy of the CAR T therapy and are only given following an established diagnosis, which may be too late. In addition, a proportion of patients with ICANS go on to develop cerebral oedema. For these reasons, understanding and predicting ICANS would have significant potential benefits for patients receiving CAR T. My project will longitudinally characterize the neurocognitive deficits before, during and after development of ICANS. To do this, I will use a battery of cognitive tests, originally developed for patients with stroke, which are especially sensitive to language impairment. I will also measure cytokine profiles and neurodegenerative markers at several timepoints to ascertain whether these track particular neurocognitive parameters. These experiments will allow me to characterise ICANS more fully and to define any risk factors and long-term deficits. Most importantly, these experiments may allow the early prediction of ICANS development which would have significant implications for the development of treatment strategies.