Clinicopathologic Findings in Fatal Neurotoxicity After Adoptive Immunotherapy With CD19-Directed CAR T-Cells

摘要

Chimeric antigen receptors (CARs) incorporate antigen-recognition moieties that endow an autologous polyclonal T-cell population with major histocompatibility complex-unrestricted specificity against a tumor cell-antigen such as the B-cell-antigen CD19. Several clinical trials have shown high response rates for immunotherapy with CD19-directed CAR T-cells in patients with large B-cell lymphoma,1 B-cell lymphoblastic leukemia,2 and mantle-cell lymphoma.3 However, broader success of CAR T-cell therapy is hampered by unique adverse effects including cytokine release syndrome (CRS) and neurotoxicity which is also denoted by the term “immune effector cell–associated neurotoxicity syndrome” (ICANS). Whereas CRS is a well-characterized phenotype mimicking sepsis and therapeutic agents are available to alleviate symptoms, pathogenesis and management of neurotoxicity are less well understood. Although considered a rare event, fatalities in the setting of neurologic symptoms following CAR T-cell infusion have been described.4 Data on neuropathological findings are therefore limited. We present a case of fatal neurotoxicity after treatment with CD19-directed CAR T-cells, outline neuropathological findings, and interpret our findings in light of novel pathogenetic models of ICANS (particularly focusing on evidence for cross-reactivity of CAR T-cells against brain mural cells in our case).