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Cancer Discov. 2017 Dec;7(12):1404-1419. doi: 10.1158/2159-8290.CD-17-0698. Epub 2017 Oct 12.

Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells.

Author information

1
Department of Neurology, University of Washington, Seattle, Washington.
2
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
3
Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
4
Juno Therapeutics, Seattle, Washington.
5
Department of Pathology, University of Washington, Seattle, Washington.
6
Department of Medicine, University of Washington, Seattle, Washington.
7
Bloodworks Northwest Research Institute, Seattle, Washington.
8
Department of Radiology, University of Washington, Seattle, Washington.
9
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. cturtle@fhcrc.org.

Abstract

Lymphodepletion chemotherapy followed by infusion of CD19-targeted chimeric antigen receptor-modified T (CAR-T) cells can be complicated by neurologic adverse events (AE) in patients with refractory B-cell malignancies. In 133 adults treated with CD19 CAR-T cells, we found that acute lymphoblastic leukemia, high CD19+ cells in bone marrow, high CAR-T cell dose, cytokine release syndrome, and preexisting neurologic comorbidities were associated with increased risk of neurologic AEs. Patients with severe neurotoxicity demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier (BBB) permeability. The permeable BBB failed to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFNγ, which induced brain vascular pericyte stress and their secretion of endothelium-activating cytokines. Endothelial activation and multifocal vascular disruption were found in the brain of a patient with fatal neurotoxicity. Biomarkers of endothelial activation were higher before treatment in patients who subsequently developed grade ≥4 neurotoxicity.Significance: We provide a detailed clinical, radiologic, and pathologic characterization of neurotoxicity after CD19 CAR-T cells, and identify risk factors for neurotoxicity. We show endothelial dysfunction and increased BBB permeability in neurotoxicity and find that patients with evidence of endothelial activation before lymphodepletion may be at increased risk of neurotoxicity. Cancer Discov; 7(12); 1404-19. ©2017 AACR.See related commentary by Mackall and Miklos, p. 1371This article is highlighted in the In This Issue feature, p. 1355.

PMID:
29025771
PMCID:
PMC5718945
DOI:
10.1158/2159-8290.CD-17-0698
[Indexed for MEDLINE]
Free PMC Article

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