Li et al. identified CAR-stimulated trogocytosis (transfer of surface molecules between cells) of target antigens from tumor cells (e.g., CD19) as a significant limitation facing effective use of CAR-NK cells, as it led to lower antigen density on tumor targets and fratricide of antigen-acquiring CAR-NK cells by non-antigen-containing CAR-NK siblings. Additional insertion of an inhibitory CAR (iCAR) comprising an scFv recognizing a ubiquitous NK surface target (CS1) fused to the intracellular inhibitory ITIM motif from KIR2DL1 prevented killing of iCAR-containing NK-CAR cells presenting trogocytosed antigens, leading to improved overall survival.
Contributed by Ed Fritsch
ABSTRACT: Trogocytosis is an active process that transfers surface material from targeted to effector cells. Using multiple in vivo tumor models and clinical data, we report that chimeric antigen receptor (CAR) activation in natural killer (NK) cells promoted transfer of the CAR cognate antigen from tumor to NK cells, resulting in (1) lower tumor antigen density, thus impairing the ability of CAR-NK cells to engage with their target, and (2) induced self-recognition and continuous CAR-mediated engagement, resulting in fratricide of trogocytic antigen-expressing NK cells (NK(TROG+)) and NK cell hyporesponsiveness. This phenomenon could be offset by a dual-CAR system incorporating both an activating CAR against the cognate tumor antigen and an NK self-recognizing inhibitory CAR that transferred a 'don't kill me' signal to NK cells upon engagement with their TROG(+) siblings. This system prevented trogocytic antigen-mediated fratricide, while sparing activating CAR signaling against the tumor antigen, and resulted in enhanced CAR-NK cell activity.
Author Info: (1) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. UTHealth Graduate School of Biomedical Scienc
Author Info: (1) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (5) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (6) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (7) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Biosciences Institute, University of Sao Paulo, Sao Paulo, Brazil. Department of Stem Cell Transplantation and Cellular Therapy, Hospital Israelita Albert Einstein, Sao Paulo, Brazil. (8) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (9) Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX, USA. (10) Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX, USA. (11) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (12) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (13) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (14) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (15) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (16) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (17) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (18) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (19) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (20) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Medicine III: Hematology and Oncology, Technical University of Munich, Munich, Germany. (21) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (22) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (23) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (24) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (25) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (26) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (27) Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (28) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (29) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (30) Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX, USA. (31) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (32) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. KRezvani@mdanderson.org.
