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

• Published in: Journal of immunotherapy (1997) Vol. 41; no. 7; p. 350
• Main Authors: Shalabi, Haneen, Wolters, Pamela L, Martin, Staci, Toledo-Tamula, Mary Anne, Roderick, Marie Claire, Struemph, Kari, Kane, Eli, Yates, Bonnie, Delbrook, Cindy, Mackall, Crystal L, Lee, Daniel W, Fry, Terry J, Shah, Nirali N
• Format: Journal Article
• Language: English
• Published: United States 01.09.2018
• Subjects: Adolescent; Adult; Brain - drug effects; Child; Confusion; Cytokines - blood; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions - diagnosis; Female; Hallucinations; Humans; Immunotherapy, Adoptive - adverse effects; Immunotherapy, Adoptive - methods; Magnetic Resonance Imaging; Male; Mental Status and Dementia Tests; Neurotoxicity Syndromes - diagnosis; Neurotoxicity Syndromes - etiology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - immunology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - therapy; Prospective Studies; Recurrence; Sialic Acid Binding Ig-like Lectin 2 - immunology; Spine - pathology; Young Adult
• ISSN: 1537-4513
• DOI: 10.1097/CJI.0000000000000241

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.