Systematic Evaluation of Neurotoxicity in Children and Young Adults Undergoing CD22 Chimeric Antigen Receptor-T Cell Therapy

摘要

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 pre- and post-therapy and a baseline brain MRI. Brief cognitive evaluations, assessing four domains (attention, working memory, cognitive flexibility, and processing speed), were administered pre- and post-infusion. A newly-developed CAR-T-specific neurologic symptom checklist (NSC) was completed by caregivers at three designated time-points. Serial serum cytokine levels were compared with neurotoxicity symptoms and severity. The majority of the first twenty-two consecutively-treated subjects (ages 7-30) demonstrated stable or improved cognitive test scores following therapy and no irreversible neurotoxicity, despite CAR-T related anti-leukemic 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.