TY - JOUR
T1 - Single-cell imaging of CAR T cell activity in vivo reveals extensive functional and anatomical heterogeneity
AU - Cazaux, Marine
AU - Grandjean, Capucine L
AU - Lemaître, Fabrice
AU - Garcia, Zacarias
AU - Beck, Richard J
AU - Milo, Idan
AU - Postat, Jérémy
AU - Beltman, Joost B
AU - Cheadle, Eleanor J
AU - Bousso, Philippe
N1 - © 2019 Cazaux et al.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
U2 - 10.1084/jem.20182375
DO - 10.1084/jem.20182375
M3 - Article
C2 - 30936262
SN - 0022-1007
JO - The Journal of experimental medicine
JF - The Journal of experimental medicine
ER -