By probing human brain scRNAseq datasets and performing IHC, Parker and Migliorini et al. showed that CD19, regarded as B cell-specific, is expressed by human brain vascular smooth muscle cells and pericytes, the mural cells lining vessels and endothelium comprising the BBB. CD19 expression coincided with the temporal development and localization of brain mural cells and contained the epitope targeted by CD19 CAR T cell and BiTE therapies, inferring a basis for their neurotoxicity. Despite the low frequency of CD19+ mouse (m) mural brain cells, infused mCD19-CAR-T cells disrupted the BBB and depleted pericytes in B cell-deficient mice.
Contributed by Paula Hochman
ABSTRACT: 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.