Neurotoxicity After CAR T-cell Therapy May Be Associated With Endothelial Activation

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Endothelial activation is associated with capillary leak, blood coagulation abnormalities, and blood-brain barrier disruption.
Endothelial activation is associated with capillary leak, blood coagulation abnormalities, and blood-brain barrier disruption.

Patients with endothelial activation prior to lymphodepletion chemotherapy are at greater risk of experiencing neurologic adverse events (AEs) after being treated with chimeric antigen receptor (CAR) T-cell therapy.

Although the development of CAR T-cell therapy has led to high response rates among patients with acute lymphoblastic leukemia (ALL), patients being treated with this novel treatment are presenting with severe neurotoxicity.


The researchers assessed data from a clinical study in which 133 patients with relapsed/refractory B-cell ALL (B-ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL) received lymphodepletion chemotherapy followed by CD19 CAR-T therapy. Within 28 days of CAR-T cell infusion, 53 patients (40%) developed 1 or more grade 1 or greater neurologic AEs, of whom 48 also had cytokine release syndrome (CRS).

Analysis showed that younger patients (P =.094), patients with B-ALL (P =.084), high tumor burden (P =.072) and CD19+ cells in bone marrow (P =.062), and high CAR T-cell dose (P <.0001) experienced higher rates of neurotoxicity. Patients who developed grade 3 or greater neurotoxicity presented with more severe CRS (P <.0001), and were more likely have had early onset CRS.


Endothelial activation, which is associated with capillary leak, blood coagulation abnormalities, and disruption of the blood-brain barrier, was also observed in patients who experienced severe CRS and neurotoxicity. Patients who developed grade 4 or greater neurotoxicity had higher levels of biomarkers indicating endothelial activation prior to treatment.

A limitation of this analysis was that study patients only received JCAR014 CAR T-cell therapy, and results may not pertain to other forms of CAR T-cell therapy.

The authors concluded “identification of the pathologic characteristics of neurotoxicity, related biomarkers, and risk factors will facilitate further studies of the mechanisms of neurotoxicity and will enhance efforts to safely deliver CAR-T cell immunotherapy.”

Reference

Gust J, Hay KA, Hanafi LA, et al. Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells [published online October 12, 2017]. Cancer Disc. doi: 10.1158/2159-8290.CD-17-0698

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