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Systematic Evaluation of Neurotoxicity in Children and Young Adults Undergoing CD22 Chimeric Antigen Receptor T-Cell Therapy JOURNAL OF IMMUNOTHERAPY Shalabi, H., Wolters, P. L., Martin, S., Toledo-Tamula, M., Roderick, M., Struemph, K., Kane, E., Yates, B., Delbrook, C., Mackall, C. L., Lee, D. W., Fry, T. J., Shah, N. N. 2018; 41 (7): 350–58

Abstract

Neurotoxicity associated with CAR-T cell therapy can be life-threatening. With rapid development of CAR-T therapies, a systematic method is needed to identify and monitor symptoms of neurotoxicity, elucidate potential etiologies, and compare toxicity across trials. This paper presents a systematic evaluation developed and used to prospectively assess neurotoxicity in our phase I anti-CD22 CAR-T-cell trial and describes the symptoms of neurotoxicity identified using this methodology. Central nervous system (CNS) studies included routine lumbar punctures performed for disease evaluation pretherapy and posttherapy and a baseline brain MRI. Brief cognitive evaluations, assessing 4 domains (attention, working memory, cognitive flexibility, and processing speed), were administered preinfusion and postinfusion. A newly developed CAR-T-specific neurological symptom checklist (NSC) was completed by caregivers at 3 designated time-points. Serial serum cytokine levels were compared with neurotoxicity symptoms and severity. The majority of the first 22 consecutively treated subjects (ages, 7-30) demonstrated stable or improved cognitive test scores following therapy and no irreversible neurotoxicity, despite CAR-T-related antileukemic response, cytokine release syndrome, and trafficking of CAR-T cells to the CSF. The NSC allowed us to document the type and timing of symptoms and explore the etiology of neurotoxicity associated with CD22 CAR-T therapy. Cytokine profiling demonstrated that more concerning symptoms of neurotoxicity, such as hallucination and disorientation, were significantly associated with higher serum cytokine levels, supporting the hypothesis of inflammation-driven neurotoxicity. Systematic assessments of neurotoxicity were feasible in acutely ill children and young adults and served to characterize and monitor the symptoms associated with CAR-T therapy. We recommend these evaluations be incorporated into future immunotherapy protocols.

View details for PubMedID 30048343

View details for PubMedCentralID PMC6086728