PROJECT SUMMARY Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of hematologic malignancies, resulting in remarkable disease response rates. Yet, the unprecedented efficacy of CAR-T cell therapy is limited by unique toxicities. Among them, immune effector cell-associated neurotoxicity syndrome (ICANS), a specific type of neurotoxicity, found in up to 70% of patients treated with CAR-T cells, consists of neurologic symptoms including encephalopathy, aphasia, seizures, which often develop acutely. While most cases of ICANS appear to resolve within the first month post-CAR-T therapy, a subset of patients develop delayed or chronic neurologic symptoms. However, the acute and chronic neurologic sequelae of CAR-T therapy are poorly understood, making this an urgent and unmet clinical need. Our preliminary data suggest that the KYN pathway is a critical link between systemic inflammation and acute ICANS. Also, changes in blood markers of neuroaxonal and glial injury have been reported during ICANS, suggesting that these are relevant markers. Our ongoing pilot study assessing neurocognitive and quantitative neuroimaging outcomes in lymphoma patients treated with CAR-T cell therapy suggest a decline in verbal memory as well as decreases in white matter and resting state functional connectivity from pre- to 3-4 months post-CAR-T. Taken together, these findings suggest that a deeper understanding of ICANS and its chronic impact is of utmost relevance given the growing use of CAR-T therapy. Aim 1 will investigate the molecular pathogenesis of acute ICANS using our large biobank of longitudinally collected samples from 135 lymphoma patients treated with CAR-T cells. We will assess changes in the KYN pathway neuroactive metabolites, immune cell transcriptomes, proinflammatory proteins, and markers of neuronal and glial damage, pre- and within the first month post-CAR-T, to explore their association with the development of acute ICANS. Aim 2 will assess neurocognitive function and structural and functional neuroimaging prospectively in 120 additional lymphoma patients, pre-treatment, as well as 3- and 6-months post-CAR-T, and their association with acute ICANS. We will explore acute and longitudinal changes in metabolites, proinflammatory cytokines, and neuronal/glial damage markers, and their association with neurocognitive and neuroimaging outcomes. This project involves a multi-disciplinary team with complementary expertise in neurology, immunology, neuropsychology, neuroradiology, neuroimaging, bioinformatics, and biostatistics with extensive experience in cancer research. We are uniquely positioned to conduct this ambitious research plan, and our results will offer novel insights into the pathogenesis of acute neurotoxicity and provide phenotypic characterization of chronic neurologic sequelae after CAR-T cell therapy. By improving the current scientific understanding and clinical management of ICANS, our study will contribute to identifying patients at risk for chronic neurotoxicity, improving clinical decision-making, and developing interventions to prevent/minimize treatment-related sequelae without decreasing CAR-T therapy efficacy.

PROJECT NARRATIVE CAR-T cell therapy has revolutionized the treatment of lymphoma, but its unprecedented efficacy is often limited by acute ICANS (Immune Effector Cell Associated Neurotoxicity Syndrome), which may increase the risk for neurocognitive dysfunction; however, the chronic neurologic impact of CAR-T cell therapy has not been studied systematically. Our proposal will describe the molecular, neurocognitive and neuroimaging features of acute and chronic neurotoxicity through retrospective and prospective cohorts of lymphoma patients treated with CAR-T cells, with the overarching goal of providing a comprehensive characterization of neurotoxicity and improving current trial and therapeutic design in this vulnerable set of patients.