Single-cell imaging of CAR T cell activity in vivo reveals extensive functional and anatomical heterogeneity
Cheadle, Eleanor, J
AffiliationDynamics of Immune Responses Unit, Equipe Labellisee Ligue Contre le Cancer, Institut Pasteur, INSERM U1223, Paris, France
MetadataShow full item record
AbstractCAR 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.
CitationCazaux 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.
JournalThe Journal of Experimental Medicine
- Long-term in vivo microscopy of CAR T cell dynamics during eradication of CNS lymphoma in mice.
- Authors: Mulazzani M, Fräßle SP, von Mücke-Heim I, Langer S, Zhou X, Ishikawa-Ankerhold H, Leube J, Zhang W, Dötsch S, Svec M, Rudelius M, Dreyling M, von Bergwelt-Baildon M, Straube A, Buchholz VR, Busch DH, von Baumgarten L
- Issue date: 2019 Nov 26
- A tandem CD19/CD20 CAR lentiviral vector drives on-target and off-target antigen modulation in leukemia cell lines.
- Authors: Schneider D, Xiong Y, Wu D, Nӧlle V, Schmitz S, Haso W, Kaiser A, Dropulic B, Orentas RJ
- Issue date: 2017
- Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity.
- Authors: Ghosh A, Smith M, James SE, Davila ML, Velardi E, Argyropoulos KV, Gunset G, Perna F, Kreines FM, Levy ER, Lieberman S, Jay HV, Tuckett AZ, Zakrzewski JL, Tan L, Young LF, Takvorian K, Dudakov JA, Jenq RR, Hanash AM, Motta AC, Murphy GF, Liu C, Schietinger A, Sadelain M, van den Brink MR
- Issue date: 2017 Feb
- A Syngeneic Mouse B-Cell Lymphoma Model for Pre-Clinical Evaluation of CD19 CAR T Cells.
- Authors: Kueberuwa G, Zheng W, Kalaitsidou M, Gilham DE, Hawkins RE
- Issue date: 2018 Oct 16
- Single-cell multiplexed cytokine profiling of CD19 CAR-T cells reveals a diverse landscape of polyfunctional antigen-specific response.
- Authors: Xue Q, Bettini E, Paczkowski P, Ng C, Kaiser A, McConnell T, Kodrasi O, Quigley MF, Heath J, Fan R, Mackay S, Dudley ME, Kassim SH, Zhou J
- Issue date: 2017 Nov 21