Single-Cell Analyses Identify Brain Mural Cells Expressing CD19 as Potential Off-Tumor Targets for CAR-T Immunotherapies. Parker, K. R, Migliorini, D., Perkey, E., Yost, K. E, Bhaduri, A., Bagga, P., Haris, M., Wilson, N. E, Liu, F., Gabunia, K., Scholler, J., Montine, T. J, Bhoj, V. G, Reddy, R., Mohan, S., Maillard, I., Kriegstein, A. R, June, C. H, Chang, H. Y, Posey, J., & Satpathy, A. T Cell, 183(1):126–142.e17, September, 2020.
abstract   bibtex   
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.
@ARTICLE{Parker2020-tr,
  title    = "{Single-Cell} Analyses Identify Brain Mural Cells Expressing
              {CD19} as Potential {Off-Tumor} Targets for {CAR-T}
              Immunotherapies",
  author   = "Parker, Kevin R and Migliorini, Denis and Perkey, Eric and Yost,
              Kathryn E and Bhaduri, Aparna and Bagga, Puneet and Haris,
              Mohammad and Wilson, Neil E and Liu, Fang and Gabunia, Khatuna
              and Scholler, John and Montine, Thomas J and Bhoj, Vijay G and
              Reddy, Ravinder and Mohan, Suyash and Maillard, Ivan and
              Kriegstein, Arnold R and June, Carl H and Chang, Howard Y and
              Posey, Jr, Avery D and Satpathy, Ansuman T",
  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.",
  journal  = "Cell",
  volume   =  183,
  number   =  1,
  pages    = "126--142.e17",
  month    =  sep,
  year     =  2020,
  language = "en"
}

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