Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells

By J. Gust, K. Hay, L. Hanafi, Daniel H. Li, David Myerson, L. Gonzalez-Cuyar, Cecilia Yeung, W. Liles, M. Wurfel, José A. López and 8 more. Cancer Discovery, 2017

1,193 citations recorded by the source corpus.

Lymphodepletion chemotherapy followed by infusion of CD19-targeted chimeric antigen receptor (CAR)-modified T (CAR-T) cells can be complicated by neurologic adverse events (AEs) 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 CSF from high concentrations of systemic cytokines including IFN-γ, 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.

Subfields: Biomedical Engineering, Oncology

View Paper: https://www.semanticscholar.org/paper/d8f7f73fe1b94485dd7ec8b169b3e9dc839a26df

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Citations in the corpus

Standard-of-Care Axicabtagene Ciloleucel for Relapsed or Refractory Large B-Cell Lymphoma: Results From the US Lymphoma CAR T Consortium. (2020, background): “It is likely that higher tumor burden may increase the risk of neurotoxicity by promoting greater expansion of CAR T cells.(6,17) The large sample size of this study also allowed analysis of covariates associated with efficacy.”
B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. (2019, background): “Neurotoxicity has been associated with early onset of CRS and rapid elevation of inflammatory cytokines both within the serum and CNS, perhaps leading to increased CNS vascular permeability (32).”
Recent advances in CAR T-cell toxicity: Mechanisms, manifestations and management (2018, background): “Severe neurologic toxicity occurs almost exclusively in patients who develop CRS and usually occurs after the first fever [52,56].”
Clinical and Biologic Correlates of Neurotoxicity Associated with CAR T Cell Therapy in Patients with B-cell Acute Lymphoblastic Leukemia (B-ALL) (2018, background): “An association between angiopoietin levels and CAR-associated neurotoxicity has recently been reported with a 4-1BB– containing CAR construct (11).”
The blood–brain barrier in systemic infection and inflammation (2021, background): “There is evidence of BBB leakage to albumin and cells as well as endothelial cell destruction [125].”
Cytokine release syndrome (2018, background): “A recent study found that neurotoxicity after immunotherapy with CD19-targeted CAR T cells was accompanied by findings consistent with endothelial activation [64].”
ASBMT Consensus Grading for Cytokine Release Syndrome and Neurological Toxicity Associated with Immune Effector Cells (2018, background): “In a recent report, Gust et al [30] suggested a role for endothelial activation and blood-brain barrier disruption in the pathophysiology of neurotoxicity.”