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Ann Neurol. 2019 Jul;86(1):42-54. doi: 10.1002/ana.25502. Epub 2019 May 27.

Glial injury in neurotoxicity after pediatric CD19-directed chimeric antigen receptor T cell therapy.

Author information

1
Seattle Children's Division of Pediatric Neurology, Department of Neurology, University of Washington, Seattle, WA.
2
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA.
3
Seattle Children's Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA.
4
Juno Therapeutics, Seattle, WA.
5
Seattle Children's Division of Radiology, Seattle, WA.
6
Department of Pathology, University of Alabama, Birmingham, AL.
7
Department of Pathology, University of California San Diego, San Diego, CA.
8
Seattle Children's Division of Hematology-Oncology, Seattle, WA.

Abstract

OBJECTIVE:

To test whether systemic cytokine release is associated with central nervous system inflammatory responses and glial injury in immune effector cell-associated neurotoxicity syndrome (ICANS) after chimeric antigen receptor (CAR)-T cell therapy in children and young adults.

METHODS:

We performed a prospective cohort study of clinical manifestations as well as imaging, pathology, CSF, and blood biomarkers on 43 subjects ages 1 to 25 who received CD19-directed CAR/T cells for acute lymphoblastic leukemia (ALL).

RESULTS:

Neurotoxicity occurred in 19 of 43 (44%) subjects. Nine subjects (21%) had CTCAE grade 3 or 4 neurological symptoms, with no neurotoxicity-related deaths. Reversible delirium, headache, decreased level of consciousness, tremor, and seizures were most commonly observed. Cornell Assessment of Pediatric Delirium (CAPD) scores ≥9 had 94% sensitivity and 33% specificity for grade ≥3 neurotoxicity, and 91% sensitivity and 72% specificity for grade ≥2 neurotoxicity. Neurotoxicity correlated with severity of cytokine release syndrome, abnormal past brain magnetic resonance imaging (MRI), and higher peak CAR-T cell numbers in blood, but not cerebrospinal fluid (CSF). CSF levels of S100 calcium-binding protein B and glial fibrillary acidic protein increased during neurotoxicity, indicating astrocyte injury. There were concomitant increases in CSF white blood cells, protein, interferon-γ (IFNγ), interleukin (IL)-6, IL-10, and granzyme B (GzB), with concurrent elevation of serum IFNγ IL-10, GzB, granulocyte macrophage colony-stimulating factor, macrophage inflammatory protein 1 alpha, and tumor necrosis factor alpha, but not IL-6. We did not find direct evidence of endothelial activation.

INTERPRETATION:

Our data are most consistent with ICANS as a syndrome of systemic inflammation, which affects the brain through compromise of the neurovascular unit and astrocyte injury. ANN NEUROL 2019.

PMID:
31074527
DOI:
10.1002/ana.25502

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