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

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    Authors
    Cazaux, M
    Grandjean, CL
    Lemaitre, F
    Garcia, Z
    Beck, RJ
    Milo, I
    Postat, J
    Beltman, JB
    Cheadle, Eleanor J
    Bousso, P
    Affiliation
    Dynamics of Immune Responses Unit, Equipe Labellisee Ligue Contre le Cancer, Institut Pasteur, INSERM U1223, Paris, France
    Issue Date
    2019
    
    Metadata
    Show full item record
    Abstract
    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.
    Citation
    Cazaux M, Grandjean CL, Lemaitre F, Garcia Z, Beck RJ, Milo I, et al. Single-cell imaging of CAR T cell activity in vivo reveals extensive functional and anatomical heterogeneity. J Exp Med. 2019 Apr 1.
    Journal
    The Journal of Experimental Medicine
    URI
    http://hdl.handle.net/10541/621736
    DOI
    10.1084/jem.20182375
    PubMed ID
    30936262
    Additional Links
    https://dx.doi.org/10.1084/jem.20182375
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1084/jem.20182375
    Scopus Count
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    All Paterson Institute for Cancer Research

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