A Mouse Model of Neurotoxicity Induced by Human CD19-Specific CAR T-cells: CAR T-cells Accumulate in the Subarachnoid Space Prior to Trafficking into the Brain Parenchyma 3807

Abstract Description Immune cell-associated neurotoxicity syndrome (ICANS) is a common morbidity associated with human CD19-specific chimeric antigen receptor T-cell (CAR19) immunotherapy. The etiology of ICANS is not well understood but is thought to involve breakdown of the blood-brain barrier (BBB) and subsequent entry of proinflammatory cytokines and CAR19 cells into the brain parenchyma. To understand how CAR19 therapy leads to ICANS, we developed a human CD19 transgenic (hCD19Tg) mouse model that replicates the anti-tumor efficacy and all reported toxicities – including ICANS - associated with CAR19 clinical therapy. Although the BBB is compromised in our model, it does not appear to be the major entry site of CAR19 cells. Rather, two-photon microscopy reveals that CAR19 cells first accumulate in the subarachnoid space and then migrate down into the parenchyma through perivascular spaces. Co-injected control CAR T-cells also accumulate in the subarachnoid space but do not migrate into the parenchyma, suggesting trafficking is antigen-specific. We are testing the hypotheses that: 1) accumulation of CAR19 cells in the subarachnoid space reflects their localization to the subarachnoid lymphatic-like membrane (SLYM) and 2) their subsequent migration into the parenchyma through the perivasculature is driven via recognition of hCD19 on mural cells. By understanding how CAR19 cells enter the brain, we hope to develop strategies to blunt or prevent ICANS. Funding Sources Supported by NIH/NCI R01 CA263090 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)