Clinical and Biologic Correlates of Neurotoxicity Associated with CAR T Cell Therapy in Patients with B-cell Acute Lymphoblastic Leukemia (B-ALL)

By B. Santomasso, Jae H. Park, Darin Salloum, I. Rivière, J. Flynn, E. Mead, E. Halton, Xiuyan Wang, B. Senechal, Terence J. Purdon and 11 more. Cancer Discovery, 2018

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CD19-specific chimeric antigen receptor (CAR) T cell therapy is highly effective against relapsed or refractory acute lymphoblastic leukemia (ALL), but is hindered by neurotoxicity. In 53 adult patients with ALL, we found a significant association of severe neurotoxicity with high pretreatment disease burden, higher peak CAR T cell expansion and early and higher elevations of proinflammatory cytokines in blood. Patients with severe neurotoxicity had evidence of blood-cerebrospinal fluid (CSF) barrier disruption correlating with neurotoxicity grade without association with CSF white blood cell count or CAR T-cell quantity in CSF. Proinflammatory cytokines were enriched in CSF during severe neurotoxicity with disproportionately high levels of IL6, IL8, MCP1 and IP10, suggesting central nervous system (CNS)-specific production. Seizures, seizure-like activity, myoclonus and neuroimaging characteristics suggested excitatory neurotoxicity, and we found elevated levels of endogenous excitatory agonists in CSF during neurotoxicity.

Subfields: Oncology, Physiology

View Paper: https://www.semanticscholar.org/paper/4d904ce98077532fe4246f31109804e57076a764

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Citations in the corpus

Engineering strategies to overcome the current roadblocks in CAR T cell therapy (2019, background): “…burden and can, therefore, be attenuated by paradoxically decreasing the number of cells infused in patients with high-volume disease; however, this association is inexact 3,61 , and fundamental modifications of CAR designs might be a better approach to ameliorate cytokine-related toxicities.”
ASBMT Consensus Grading for Cytokine Release Syndrome and Neurological Toxicity Associated with Immune Effector Cells (2018, background): “Several reports suggest a role for proin ﬂ ammatory cytokines and myeloid cells besides activated T cells [2,18,29,31-33].”