PMID- 28725044 OWN - NLM STAT- MEDLINE DCOM- 20190102 LR - 20210103 IS - 1476-5551 (Electronic) IS - 0887-6924 (Print) IS - 0887-6924 (Linking) VI - 32 IP - 2 DP - 2018 Feb TI - Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. PG - 520-531 LID - 10.1038/leu.2017.226 [doi] AB - Chimeric antigen receptors (CARs) have been used to redirect the specificity of autologous T cells against leukemia and lymphoma with promising clinical results. 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 marked prolongation of survival in a xenograft Raji lymphoma murine model. Interleukin-15 (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. FAU - Liu, E AU - Liu E AD - Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX, USA. FAU - Tong, Y AU - Tong Y AD - Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX, USA. FAU - Dotti, G AU - Dotti G AD - Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA. FAU - Shaim, H AU - Shaim H AD - Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX, USA. FAU - Savoldo, B AU - Savoldo B AD - Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA. FAU - Mukherjee, M AU - Mukherjee M AD - The Center for Human Immunobiology, Baylor College of Medicine, Houston, TX, USA. FAU - Orange, J AU - Orange J AD - The Center for Human Immunobiology, Baylor College of Medicine, Houston, TX, USA. FAU - Wan, X AU - Wan X AD - Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX, USA. FAU - Lu, X AU - Lu X AD - Department of Hematopathology, MD Anderson Cancer Center, Houston, TX, USA. FAU - Reynolds, A AU - Reynolds A AD - Department of Hematopathology, MD Anderson Cancer Center, Houston, TX, USA. FAU - Gagea, M AU - Gagea M AD - Department of Veterinary Medicine & Surgery, MD Anderson Cancer Center, Houston, TX, USA. FAU - Banerjee, P AU - Banerjee P AD - Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX, USA. FAU - Cai, R AU - Cai R AD - Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX, USA. FAU - Bdaiwi, M H AU - Bdaiwi MH AD - Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX, USA. FAU - Basar, R AU - Basar R AD - Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX, USA. FAU - Muftuoglu, M AU - Muftuoglu M AD - Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX, USA. FAU - Li, L AU - Li L AD - Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX, USA. FAU - Marin, D AU - Marin D AD - Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX, USA. FAU - Wierda, W AU - Wierda W AD - Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA. FAU - Keating, M AU - Keating M AD - Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA. FAU - Champlin, R AU - Champlin R AD - Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX, USA. FAU - Shpall, E AU - Shpall E AD - Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX, USA. FAU - Rezvani, K AU - Rezvani K AD - Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX, USA. LA - eng GR - P30 CA016086/CA/NCI NIH HHS/United States GR - P30 CA016672/CA/NCI NIH HHS/United States GR - R01 AI067946/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20170720 PL - England TA - Leukemia JT - Leukemia JID - 8704895 RN - 0 (Antigens, CD19) RN - 0 (CD19 molecule, human) RN - 0 (IL15 protein, human) RN - 0 (Interleukin-15) RN - 0 (Receptors, Chimeric Antigen) RN - EC 3.4.22.- (Caspase 9) SB - IM CIN - Cancer Discov. 2017 Oct;7(10):OF2. PMID: 28877899 MH - Aged MH - Antigens, CD19/*immunology MH - Caspase 9/immunology MH - Cell Line, Tumor MH - Cytotoxicity, Immunologic/immunology MH - Female MH - Fetal Blood/*immunology MH - Graft vs Host Disease/immunology MH - Humans MH - Immunotherapy, Adoptive/methods MH - Interleukin-15/*immunology MH - K562 Cells MH - Killer Cells, Natural/*immunology MH - Leukemia/immunology/therapy MH - Lymphoma/immunology/therapy MH - Male MH - Middle Aged MH - Receptors, Chimeric Antigen/*immunology MH - T-Lymphocytes/immunology PMC - PMC6063081 MID - NIHMS953741 COIS- Conflict of Interest Disclosure: The authors have no conflict of interest. EDAT- 2017/07/21 06:00 MHDA- 2019/01/03 06:00 PMCR- 2019/02/01 CRDT- 2017/07/21 06:00 PHST- 2016/12/28 00:00 [received] PHST- 2017/06/20 00:00 [revised] PHST- 2017/06/28 00:00 [accepted] PHST- 2017/07/21 06:00 [pubmed] PHST- 2019/01/03 06:00 [medline] PHST- 2017/07/21 06:00 [entrez] PHST- 2019/02/01 00:00 [pmc-release] AID - leu2017226 [pii] AID - 10.1038/leu.2017.226 [doi] PST - ppublish SO - Leukemia. 2018 Feb;32(2):520-531. doi: 10.1038/leu.2017.226. Epub 2017 Jul 20.