Single-Cell Analyses Identify Brain Mural Cells Expressing CD19 as Potential Off-Tumor Targets for CAR-T Immunotherapies.

CD19-directed immunotherapies are clinically effective for treating B cell malignancies but also cause a high incidence of neurotoxicity. A subset of patients treated with chimeric antigen receptor (CAR) T cells or bispecific T cell engager (BiTE) antibodies display severe neurotoxicity, including fatal cerebral edema associated with T cell infiltration into the brain. Here, we report that mural cells, which surround the endothelium and are critical for blood-brain-barrier integrity, express CD19. We identify CD19 expression in brain mural cells using single-cell RNA sequencing data and confirm perivascular staining at the protein level. CD19 expression in the brain begins early in development alongside the emergence of mural cell lineages and persists throughout adulthood across brain regions. Mouse mural cells demonstrate lower levels of Cd19 expression, suggesting limitations in preclinical animal models of neurotoxicity. These data suggest an on-target mechanism for neurotoxicity in CD19-directed therapies and highlight the utility of human single-cell atlases for designing immunotherapies.
Competing Interests: Declaration of Interests C.H.J. and A.D.P. report intellectual property licensed to Novartis and Tmunity Therapeutics related to CAR-T cells. K.R.P., A.T.S., H.Y.C., D.M., A.D.P., and C.H.J. are listed as inventors on patent applications filed by Stanford University and the University of Pennsylvania. K.R.P. is a consultant for Maze Therapeutics. A.T.S. is a scientific founder of Immunai and receives research funding from Arsenal Biosciences. H.Y.C. is a co-founder of Accent Therapeutics and Boundless Bio and an advisor to 10x Genomics, Arsenal Biosciences, and Spring Discovery.
(Copyright © 2020 Elsevier Inc. All rights reserved.)