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

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.

Cellular therapy: Immune‐related complications

“…Of note, 82% of these patients previously received CD19 directed CAR‐T, 4 of which had neurotoxicity. Interestingly, there was significant discordance in caregiver evaluation of neurotoxicity compared to physician evaluation …”

“…Neurologic toxicity has also previously been seen in other immunotherapeutic modulators such as Blinatumomab and is also seen after CD22 directed CAR-T as well as preclinical models of GD2-directed CART. 43,81,82 The neurological deficits seen in the days and weeks after CAR-T infusion are varied, however encephalopathy is the most common severe side effect. Similar to CRS, CRES can be mild to severe.…”

“…Interestingly, there was significant discordance in caregiver evaluation of neurotoxicity compared to physician evaluation. 82 The mechanism for CAR-T-induced neurotoxicity is still poorly understood though it is likely a conglomerate of several independent pathophysiological processes. A recent mechanistic hypothesis for CRES is centered around the inflammatory mediators released by the activated CAR-T and macrophages.…”

Psychosocial care for children receiving chimeric antigen receptor (CAR) T‐cell therapy

“…Accordingly, the Cornell Assessment of Pediatric Delirium (CAPD) has been recommended as a tool to guide the diagnosis and grading of neurologic toxicity until more sensitive mechanisms are identified 6 . As symptoms of neurologic toxicity may develop and progress rapidly, systematic evaluation of cognitive function and neurologic symptoms at baseline and along the treatment trajectory is necessary and may lead to earlier identification and intervention 6,77 . Long‐term sequelae of CAR T‐cell therapy, including neurologic toxicity, are not yet well described.…”

“…75 Although there is great variability in the development, progression, and severity of symptoms, both CRS and neurotoxicity typically 6 As symptoms of neurologic toxicity may develop and progress rapidly, systematic evaluation of cognitive function and neurologic symptoms at baseline and along the treatment trajectory is necessary and may lead to earlier identification and intervention. 6,77 Long-term sequelae of CAR T-cell therapy, including neurologic toxicity, are not yet well described. Acute neurotoxicity may be a risk factor for later neuropsychiatric symptoms.…”