To overcome the intrinsic difficulty of patient-specific manufacturing of CAR-T cells, Liu et al. demonstrate in a murine xenograft model that cord-blood derived allogeneic NK cells transduced with a construct expressing a CD19-CAR, IL-15 (to promote NK cell proliferation and in vivo persistence), and a suicide gene effectively control a B-cell lymphoma without evidence of long term leukemogenesis, supporting initiation of a clinical trial.
Chimeric antigen receptors (CARs) have been used to redirect the specificity of autologous T-cells against leukemia and lymphoma with promising clinical results.(1-3) Extending this approach to allogeneic T-cells is problematic as they carry a significant risk of graft-versus-host disease (GVHD). Natural killer (NK) cells are highly cytotoxic effectors, killing their targets in a non-antigen specific manner without causing GVHD. Cord blood (CB) offers an attractive, allogeneic, off-the-self source of NK cells for immunotherapy. We transduced CB-derived NK cells with a retroviral vector incorporating the genes for CAR-CD19, IL-15 and inducible caspase-9-based suicide gene (iC9), and demonstrated efficient killing of CD19-expressing cell lines and primary leukemia cells in vitro, with dramatic prolongation of survival in a xenograft Raji lymphoma murine model. IL-15 production by the transduced CB-NK cells critically improved their function. Moreover, iC9/CAR.19/IL-15 CB-NK cells were readily eliminated upon pharmacologic activation of the iC9 suicide gene. In conclusion, we have developed a novel approach to immunotherapy using engineered CB-derived NK cells which are easy to produce, exhibit striking efficacy and incorporate safety measures to limit toxicity. This approach should greatly improve the logistics of delivering this therapy to large numbers of patients, a major limitation to current CAR-T cell therapies.Leukemia accepted article preview online, 20 July 2017. doi:10.1038/leu.2017.226.
Author Info: (1) Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX. (2) Department of Stem Cell Transplantation and Cellular Therapy, MD Ander
Author Info: (1) Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX. (2) Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX. (3) Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC. (4) Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX. (5) Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC. (6) The Center for Human Immunobiology, Baylor College of Medicine, Houston, TX. (7) The Center for Human Immunobiology, Baylor College of Medicine, Houston, TX. (8) Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX. (9) Department of Hematopathology, MD Anderson Cancer Center, Houston, TX. (10) Department of Hematopathology, MD Anderson Cancer Center, Houston, TX. (11) Department of Veterinary Medicine &Surgery, MD Anderson Cancer Center, Houston, TX. (12) Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX. (13) Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX. (14) Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC. The Center for Human Immunobiology, Baylor College of Medicine, Houston, TX. Department of Hematopathology, MD Anderson Cancer Center, Houston, TX. Department of Veterinary Medicine &Surgery, MD Anderson Cancer Center, Houston, TX. Department of Leukemia, MD Anderson Cancer Center, Houston, TX. (15) Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC. The Center for Human Immunobiology, Baylor College of Medicine, Houston, TX. Department of Hematopathology, MD Anderson Cancer Center, Houston, TX. Department of Veterinary Medicine &Surgery, MD Anderson Cancer Center, Houston, TX. Department of Leukemia, MD Anderson Cancer Center, Houston, TX. (16) Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX. (17) Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX. (18) Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX. (19) Department of Leukemia, MD Anderson Cancer Center, Houston, TX. (20) Department of Leukemia, MD Anderson Cancer Center, Houston, TX. (21) Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX. (22) Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX. (23) Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX.
