1. Single-Cell Analyses Identify Brain Mural Cells Expressing CD19 as Potential Off-Tumor Targets for CAR-T Immunotherapies
- Author
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Parker, Kevin R, Migliorini, Denis, Perkey, Eric, Yost, Kathryn E, Bhaduri, Aparna, Bagga, Puneet, Haris, Mohammad, Wilson, Neil E, Liu, Fang, Gabunia, Khatuna, Scholler, John, Montine, Thomas J, Bhoj, Vijay G, Reddy, Ravinder, Mohan, Suyash, Maillard, Ivan, Kriegstein, Arnold R, June, Carl H, Chang, Howard Y, Posey, Avery D, and Satpathy, Ansuman T
- Subjects
Biomedical and Clinical Sciences ,Immunology ,Immunization ,Neurosciences ,Vaccine Related ,Rare Diseases ,Biotechnology ,Genetics ,Aetiology ,2.1 Biological and endogenous factors ,Development of treatments and therapeutic interventions ,5.2 Cellular and gene therapies ,Neurological ,Animals ,Antibodies ,Bispecific ,Antigens ,CD19 ,B-Lymphocytes ,Blood-Brain Barrier ,Brain ,Cell Line ,Tumor ,Cytotoxicity ,Immunologic ,Epithelial Cells ,Humans ,Immunotherapy ,Immunotherapy ,Adoptive ,Mice ,Mice ,Inbred NOD ,Mice ,SCID ,Muscle ,Smooth ,Vascular ,Neoplasms ,Receptors ,Antigen ,T-Cell ,Receptors ,Chimeric Antigen ,Single-Cell Analysis ,T-Lymphocytes ,Xenograft Model Antitumor Assays ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - 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.
- Published
- 2020