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

Abstract

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.

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“…An association has been noted between higher CRS and neurotoxicity grades and serum Von Willebrand Factor (VWF), suggesting greater endothelial activation in both CRS and CRES and this was corroborated with higher levels of Angiopoietin-2 (Ang-2) 38,45 . Importantly, this work also demonstrated that pre-existing endothelial activation (prior to CAR T cell infusion, as determined by increased VWF and Ang-2:Ang-1 ratios), may be associated with increased subsequent CRS severity.…”

“…Investigation of biomarkers of severe CRS in a predominantly paediatric cohort revealed an association between low fibrinogen and grade 4 CRS in paediatric patients 35 . This was explored further in an adult cohort treated at the Fred Hutchinson Cancer Center 38,45 where grade 4 or greater CRS was associated with hypofibrinogenaemia, increased d-dimers and reduced platelets, consistent with disseminated intravascular coagulation.…”

“…This has led to the implication of rapid transfer of inflammatory cytokines from the systemic circulation into the CSF as a potential mechanism. Further, delineation of endothelial activation in severe neurotoxicity 45 may allow rational drug targeting to ameliorate CRES.…”

“…Indeed, fatal neurotoxicity was reported in 3% of adults treated with a 4-1BB domain containing CAR for a variety of B cell malignancies at the Fred Hutchison Cancer Centre in Seattle 45 .. There is great interest in determining a biomarker profile capable of predicting high risk neurotoxicity and in the same cohort of patients, a combination of fever 38.9C with IL-6 levels of >16pg/L and monocyte chemoattractant protein (MCP) 1>1344pg/L in the first 36 hours post CAR T cell infusion was associated with a very high risk of severe neurotoxicity 45 .…”

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“…[139][140][141] Initial studies often used cyclophosphamide alone for lymphodepletion, but enhanced expansion and persistence has been documented when cyclophosphamide is combined with other agents, most commonly including fludarabine. Although there has been some concern that fludarabine may have increased the risk for neurotoxicity (given its known association with neurologic events at very high doses), which is observed after CAR-T therapy (discussed in "CRES"), the predominance of the data argues against this association being causative, 142,143 and cyclophosphamide/ fludarabine chemotherapeutic regimens are widely used with both CD19-directed and other CAR-T therapies. The goal of preinfusion chemotherapy is twofold: (1) to deplete endogenous T cells that might increase the risk of T-mediated rejection of CAR-T cells, 144 and (2) to enhance CAR-T expansion in the lymphodepleted host.…”