In a mouse model of B cell lymphoma, Cazaux and Grandjean et al. used intravital imaging to study killing dynamics of anti-CD19 CAR T cells. CAR T cells in the bone marrow (BM) induced tumor apoptosis primarily through direct cellular contact with rapid (~25min) interactions and detachment, but varied in cytotoxicity and calcium signaling. In the blood, aggregates of CAR T cells with circulating tumor or B cells accumulated in the lungs. Modeling predicted that tumor regression was solely due to direct CAR T cytotoxicity. Relapsing tumors were CD19- in BM, the key site of CAR T activity, but remained CD19+ in lymph nodes, suggesting distinct immune environments.
Contributed by Alex Najibi
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.
Author Info: (1) Dynamics of Immune Responses Unit, Equipe Labellisee Ligue Contre le Cancer, Institut Pasteur, INSERM U1223, Paris, France. University Paris Diderot, Sorbonne Paris Cite, Cellu
Author Info: (1) Dynamics of Immune Responses Unit, Equipe Labellisee Ligue Contre le Cancer, Institut Pasteur, INSERM U1223, Paris, France. University Paris Diderot, Sorbonne Paris Cite, Cellule Pasteur, Paris, France. (2) Dynamics of Immune Responses Unit, Equipe Labellisee Ligue Contre le Cancer, Institut Pasteur, INSERM U1223, Paris, France. (3) Dynamics of Immune Responses Unit, Equipe Labellisee Ligue Contre le Cancer, Institut Pasteur, INSERM U1223, Paris, France. (4) Dynamics of Immune Responses Unit, Equipe Labellisee Ligue Contre le Cancer, Institut Pasteur, INSERM U1223, Paris, France. (5) Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands. (6) Dynamics of Immune Responses Unit, Equipe Labellisee Ligue Contre le Cancer, Institut Pasteur, INSERM U1223, Paris, France. (7) Dynamics of Immune Responses Unit, Equipe Labellisee Ligue Contre le Cancer, Institut Pasteur, INSERM U1223, Paris, France. University Paris Diderot, Sorbonne Paris Cite, Cellule Pasteur, Paris, France. (8) Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands. (9) 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. (10) Dynamics of Immune Responses Unit, Equipe Labellisee Ligue Contre le Cancer, Institut Pasteur, INSERM U1223, Paris, France philippe.bousso@pasteur.fr.
