CD19-Directed CAR T cells preferentially infiltrates meninges and brain parenchyma 9364

Abstract Description Chimeric antigen receptor (CAR) T cells effectively treat hematologic malignancies; however, neurotoxicity is a common complication affecting about 40% of patients. The more severe symptoms patients may experience include seizures, cerebral edema, and hemorrhage, but the mechanism leading to neurotoxicity is unknown. Through in vivo two photon imaging of immunocompetent mice that received 10 million CD19-directed, td-Tomato-labeled CAR T cells and 10 million GFP-labeled T cells without a CAR (mock T cells), we found that the majority of extravasated and actively migrating CAR T cells were in the dura and leptomeninges, with far fewer deeper down in the brain parenchyma. There were significantly more CAR T cells than mock T cells infiltrating, even after 56 days of cell administration. Similar pattern was seen in immunohistochemical staining sections. Considering that CAR T cells proliferate more than mock T cells as they encounter CD19 antigen, we conducted flow cytometry on brain, dura, spleen, and blood and found that there was a higher ratio of CAR to mock T cells in brain and dura than in spleen and whole blood. Taken together, these results show that CD19-directed CAR T cells infiltrate the brain parenchyma and meninges more than mock T cells and further investigations are needed to explore potential cues, as well as roles and consequences of CAR T cells migrating into the brain parenchyma and meninges to elucidate whether this may be causative of CAR T neurotoxicity. Funding Sources Supported by NIH R37CA275954 (PI: Juliane Gust) and NIH K08NS118138 (PI: Juliane Gust). Topic Categories Neuroimmunology (NEUR)