Single-cell imaging of CAR T cell activity in vivo reveals extensive functional and anatomical heterogeneity

CAR T cells represent a potentially curative strategy for B cell malignancies. However, the outcome and dynamics of CAR T cell interactions in distinct anatomical sites are poorly understood. Using intravital imaging, we tracked interactions established by anti-CD19 CAR T cells in B cell lymphoma-be...

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Bibliographic Details
Published in:The Journal of experimental medicine Vol. 216; no. 5; p. 1038
Main Authors: Cazaux, Marine, Grandjean, Capucine L, Lemaître, Fabrice, Garcia, Zacarias, Beck, Richard J, Milo, Idan, Postat, Jérémy, Beltman, Joost B, Cheadle, Eleanor J, Bousso, Philippe
Format: Journal Article
Language:English
Published: United States 06.05.2019
Subjects:
Animals
Antigens, CD19 - metabolism
Apoptosis
Cell Line, Tumor
Immunotherapy, Adoptive - methods
Intravital Microscopy - methods
Lung - metabolism
Lymphoma, B-Cell - pathology
Lymphoma, B-Cell - therapy
Mice
Mice, Inbred C57BL
Mice, Knockout
Models, Animal
Models, Theoretical
Receptors, Chimeric Antigen - metabolism
Recurrence
Single-Cell Analysis - methods
T-Lymphocytes - metabolism
ISSN:1540-9538, 1540-9538
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Summary:CAR T cells represent a potentially curative strategy for B cell malignancies. However, the outcome and dynamics of CAR T cell interactions in distinct anatomical sites are poorly understood. Using intravital imaging, we tracked interactions established by anti-CD19 CAR T cells in B cell lymphoma-bearing mice. Circulating targets trapped CAR T cells in the lungs, reducing their access to lymphoid organs. In the bone marrow, tumor apoptosis was largely due to CAR T cells that engaged, killed, and detached from their targets within 25 min. Notably, not all CAR T cell contacts elicited calcium signaling or killing while interacting with tumors, uncovering extensive functional heterogeneity. Mathematical modeling revealed that direct killing was sufficient for tumor regression. Finally, antigen-loss variants emerged in the bone marrow, but not in lymph nodes, where CAR T cell cytotoxic activity was reduced. Our results identify a previously unappreciated level of diversity in the outcomes of CAR T cell interactions in vivo, with important clinical implications.
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ISSN:1540-9538
1540-9538
DOI:10.1084/jem.20182375