Brain-Imaging Markers of Neurotoxicity and Long-Term Outcomes after CAR-T Cell Therapy

Project Summary CD19-directed chimeric antigen receptor (CAR)-T cell therapy for relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) induces complete remission in 70-90% of otherwise incurable patients. CAR-T cell engagement with their target antigens induces expansion of activated CAR-T cells, producing cytokines and other pro-inflammatory mediators. Unfortunately, in approximately 50% of patients this inflammatory response also produces an Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS), a serious neurotoxicity characterized by delirium, encephalopathy, dysphasia, and in severe cases, diffuse cerebral edema that can be fatal. Additionally, ICANS increases the risk for long-term cognitive impairments; possible consequences that have not been systematically studied. ICANS therefore remains a major challenge for the wider adoption of CAR-T cell therapy, creating an urgent need to mitigate or prevent ICANS, to understand its pathophysiology, and to predict its adverse long-term outcomes. We have compelling preliminary data demonstrating that several pre-infusion neuroimaging markers predict ICANS with high accuracy. Building upon these findings, we will develop a predictive algorithm in this proposal that will facilitate closer monitoring of high-risk patients, support with preventive treatments, and risk-adapted dosing of CAR-T cells. Our preliminary data also suggest that neuroimaging biomarkers serve as objective surrogates for clinical and subclinical ICANS. These markers may guide future development of targeted anti-cytokine and small molecule inhibitor-based interventions to inhibit or block neurotoxicity-specific pathways. Finally, preliminary data support our hypothesis that ICANS-induced abnormalities in attentional networks of the brain cause long-term neurocognitive impairments. Adverse outcomes are also seen in low grade neurotoxicity, suggesting a greater need than previously anticipated for cognitive and behavioral interventions in CAR-T cell patients, rather than only in patients with florid neurotoxicity. Expanding on our pilot study, we propose to conduct a prospective, longitudinal cohort study of 80 consecutive patients who receive CAR-T cell therapy for B-ALL. We will collect state-of-the-art (a) clinical assessments for ICANS and CRS, (b) multi-modal MRI to characterize brain structure, function, and metabolism, (c) peripheral blood samples for immunophenotyping using CyTOF (mass Cytometry by Time-Of-Flight) and to profile cytokines and biomarkers of blood brain barrier integrity, and (d) neurocognitive testing to characterize cognitive changes. Longitudinal data will be collected at (1) a pre- infusion baseline; and then post-infusion on (2) Day 10, when the ICANS risk is greatest, (3) Day 28, upon ICANS resolution, and (4) month 12, for long-term outcomes. These data will identify, with unparalleled inferential capacity, brain-based predictors and inflammatory mediators of ICANS, help develop brain MRI guidelines for CAR-T cell therapy, and help recommend specific cognitive training and neuroprotective strategies in patients with persistent brain deficits.