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J Exp Med. 2019 Apr 1. pii: jem.20182375. doi: 10.1084/jem.20182375. [Epub ahead of print]

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

Author information

1
Dynamics of Immune Responses Unit, Equipe Labellisée Ligue Contre le Cancer, Institut Pasteur, INSERM U1223, Paris, France.
2
University Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, Paris, France.
3
Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands.
4
Targeted Therapy Group, Manchester Cancer Research Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.
5
Dynamics of Immune Responses Unit, Equipe Labellisée Ligue Contre le Cancer, Institut Pasteur, INSERM U1223, Paris, France philippe.bousso@pasteur.fr.

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.

PMID:
30936262
DOI:
10.1084/jem.20182375

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