Endothelial Activation and Blood–Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells
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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. 1371. This article is highlighted in the In This Issue feature, p. 1355
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Therapy for cytokine release syndrome and its neurological toxicity chiefly targets IL-6, which probably originates from monocytes or activated endothelial cells.
“Treatment for CRS and associated neurotoxicity primarily targets IL-6, likely arising from monocytes or activated endothelium [1, 6, 11–17].”
From Immune reconstitution and clinical recovery following anti-CD28 antibody (TGN1412)-induced cytokine storm (2021) · cites this paper as [11]
The Discussion (page unavailable) says treatment of established neurotoxicity has largely included controlling IL-6-mediated inflammatory pathways with tocilizumab as part of CRS management. It does not identify monocytes or activated endothelial cells as the likely source of IL-6; the Results instead show that stimulated brain pericytes secrete IL-6. The Discussion also cautions that targeting IL-6R alone did not prevent neurotoxicity in some patients. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCytokine release syndrome and neurotoxicity are the most serious immune-related adverse events, and they are most prominently reported in patients given CAR-T cells.
“The most severe of these immune-related adverse events (irAEs) are cytokine release syndrome (CRS) and neurotoxicity, most prominently described in patients treated with CAR-T-cells [6–11].”
From Immune reconstitution and clinical recovery following anti-CD28 antibody (TGN1412)-induced cytokine storm (2021) · cites this paper as [11]
The Introduction (page unavailable) says CRS develops in most patients after CD19 CAR-T infusion and neurologic adverse events are frequent and can be fatal. The Results report fatal neurotoxicity in four patients. The paper does not establish that these are the most severe immune-related adverse events overall or that they are reported more prominently with CAR-T cells than with other treatments. (LLM, conf=0.82)
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- Authors
- Gust, J., Hay, K. A., Hanafi, L.-A., Li, D., Myerson, D., Gonzalez-Cuyar, L. F., Yeung, C., Liles, W. C., Wurfel, M., Lopez, J. A., Chen, J., Chung, D., Harju-Baker, S., Özpolat, T., Fink, K. R., Riddell, S. R., Maloney, D. G., & Turtle, C. J.
- Affiliations
- University of Washington (US)
- University of British Columbia (CA)
- Fred Hutch Cancer Center (US)
- Juno Therapeutics (United States) (US)
- 5Department of Pathology, University of Washington, Seattle, Washington.
- 6Department of Medicine, University of Washington, Seattle, Washington.
- Bloodworks Northwest (US)
- Corresponding author
- Turtle, Cameron J.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2017-12-01
- Volume
- 7
- Issue
- 12
- Pages
- 1404-1419
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC5718945
- OpenAlex
- W2763751953
- Cited by
- 1,400
- References
- 26
- Citations by year
- 2026: 143 · 2025: 141 · 2024: 135 · 2023: 163 · 2022: 167 · 2021: 202 · 2020: 209 · 2019: 139 · 2018: 93 · 2017: 2 · 2013: 1
- FWCI
- 53.39
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Juno Therapeutics (NCIR01 CA136551)
- Life Science Discovery Fund (NIDDKP30 DK56465, NCIP30 CA15704)
- University of British Columbia Clinical Investigator Program (R56 HL131946-01, R01 HL117639-01, R01 HL112633, R21 HL129526-01)
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- CD19 CAR T cells, neurotoxicity, blood-brain barrier permeability, endothelial activation, cytokine release syndrome, interferon-gamma, pericytes, disseminated intravascular coagulation, capillary leak syndrome, lymphocyte depletion, acute lymphoblastic leukemia, B-cell malignancies, risk factors, endothelial dysfunction, cerebrospinal fluid cytokines
- MeSH terms
- Blood-Brain Barrier, Humans, Receptors, Antigen, T-Cell, Immunotherapy, Adoptive, Treatment Outcome, Antigens, CD19
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