Modifiers of Endothelial Permeability in the Setting of CAR-t Therapy Related Immune Cell Associated Neurotoxicity Syndrome

Abstract

Background Chimeric Antigen Receptor T-cell therapy (CAR-t) for patients with relapsed or refractory B cell precursor acute lymphoblastic leukemia (ALL) is associated with high overall remission rates but also with significant complications. Cytokine release syndrome (CRS) and Immune Cell Associated Neurotoxicity Syndrome (ICANS) are life-threatening sequelae that may occur in CAR-t recipients. ICANS presents with varying symptoms ranging from confusion to seizure and cerebral edema. There is no consensus on specific biological events that incite ICANS. Blood brain barrier (BBB) permeability is altered in CD19 CAR-t therapy, but the cause of altered BBB permeability is not clear. IL6 targeted interventions that control symptoms of CRS are ineffective against ICANS, suggesting these entities have separate pathologic mechanisms. Criteria for ICANS severity grading and guidelines for supportive care management are published, but there is no universal predictor of ICANS. Identification of manipulable biologic factors to predict the onset of ICANS would represent significant progress for clinical management of ICANS. Methods We collected plasma samples from 12 adult patients with varying ICANS severity following CAR-t therapy, aged 24-74 years. Diagnoses were diffuse large B cell lymphoma (DLBCL), transformed follicular lymphoma (TFL), and primary mediastinal B cell lymphoma (PMBCL) in varying stages of progression or relapse. Pre-CAR-t, midpoint and 7 or 8 day post CAR-t samples were evaluated with multiplex cytokine arrays to quantify relative levels of 105 angiogenic cytokines. Results were compared between two groups: patients who did not develop ICANS (n=5), and patients who developed any grade of ICANS (n=7; 2 patients grade 0-2, 5 patients grade 3-4). Results There was a trend toward higher baseline relative levels of two angiogenic factors, ApoA1 and Angiogenin, in patients with ICANS relative to those without. Interestingly, ApoA1 increased over time in patients who did not develop ICANS; a 320 +/- 56 % increase in ApoA1 occurred from baseline to day 7/8. In contrast, ApoA1 decreased to 88 +/- 25% of baseline by day 7/8 in patients who developed ICANS (No ICANS vs ICANS; p=0.003). Similarly, Angiogenin increased by 289 +/- 77% over baseline by day 7/8 in patients who did not develop ICANS, while it decreased to 98 +/- 24 % of baseline by day 7/8 in patients who developed ICANS (No ICANS vs ICANS, p = 0.03). Conclusion Our data suggests that ApoA1 and Angiogenin levels at baseline, and changes in ApoA1 or Angiogenin over time, may indicate risk of ICANS. This correlation requires validation in a larger patient population as well as quantification of absolute ApoA1 and Angiogenin concentrations in blood. If ApoA1 and Angiogenin baseline levels are indeed correlated with the risk of ICANS, this may represent major progress in clinical management of ICANS.