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.
Author Info: (1) Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, Stanford University School of Medic
Author Info: (1) Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, Stanford University School of Medicine, Stanford, CA, USA. (2) Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Translational Research in Onco-Hematology and Department of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland. Electronic address: denis.migliorini@hcuge.ch. (3) Graduate Program in Cellular and Molecular Biology and Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA; Division of Hematology-Oncology, Department of Medicine and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (4) Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, Stanford University School of Medicine, Stanford, CA, USA. (5) Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA. (6) Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (7) Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Functional and Molecular Imaging Laboratory, Research Branch, Sidra Medicine, Doha, Qatar; Laboratory Animal Research Center, Qatar University, Doha, Qatar. (8) Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (9) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (10) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (11) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (12) Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. (13) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (14) Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (15) Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (16) Division of Hematology-Oncology, Department of Medicine and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (17) Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA. (18) Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (19) Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, Stanford University School of Medicine, Stanford, CA, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. (20) Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA. (21) Parker Institute for Cancer Immunotherapy, Stanford University School of Medicine, Stanford, CA, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: satpathy@stanford.edu.
