title: Donor-derived natural killer cells infused after human leukocyte antigen-haploidentical hematopoietic cell transplantation: a dose-escalation study.
abstract: The doses of donor-derived natural killer (NK) cells that can be given safely after human leukocyte antigen (HLA)-haploidentical hematopoietic cell transplantation (HCT) remain to be defined. Forty-one patients (ages 17 to 75 years) with hematologic malignancy underwent HLA-haploidentical HCT after reduced-intensity conditioning containing busulfan, fludarabine, and antithymocyte globulin. Cell donors (ages 7 to 62 years) underwent growth factor-mobilized leukapheresis for 3 to 4 days. Cells collected on the first 2 to 3 days were used for HCT, whereas those collected on the last day were CD3-depleted and cultured into NK cells using human interleukins-15 and -21. These NK cells were then infused into patients twice at 2 and 3 weeks after HCT at an escalating doses of .2 × 10(8) cells/kg of body weight (3 patients), .5 × 10(8) cells/kg (3 patients), 1.0 × 10(8) cells/kg (8 patients), and ≥ 1.0 × 10(8) cells/kg or available cells (27 patients). At all dose levels, no acute toxicity was observed after NK cell infusion. After HLA-haploidentical HCT and subsequent donor NK cell infusion, when referenced to 31 historical patients who had undergone HLA-haploidentical HCT after the same conditioning regimen but without high-dose NK cell infusion, there was no significant difference in the cumulative incidences of major HCT outcomes, including engraftment (absolute neutrophil count ≥ 500/μL, 85% versus 87%), grade 2 to 4 acute graft-versus-host disease (GVHD, 17% versus 16%), moderate to severe chronic GVHD (15% versus 10%), and transplantation-related mortality (27% versus 19%). There was, however, a significant reduction in leukemia progression (74% to 46%), with post-transplantation NK cell infusion being an independent predictor for less leukemia progression (hazard ratio, .527). Our findings showed that, when given 2 to 3 weeks after HLA-haploidentical HCT, donor-derived NK cells were well tolerated at a median total dose of 2.0 × 10(8) cells/kg. In addition, they may decrease post-transplantation progression of acute leukemia.
authors: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea. Electronic address: ipchoi@kribb.re.kr.
authors: Inpyo
authors: I
authors: Choi
authors: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
authors: Suk Ran
authors: SR
authors: Yoon
authors: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
authors: Soo-Yeon
authors: SY
authors: Park
authors: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
authors: Hanna
authors: H
authors: Kim
authors: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
authors: Sol-Ji
authors: SJ
authors: Jung
authors: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
authors: Ye Jin
authors: YJ
authors: Jang
authors: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
authors: Minho
authors: M
authors: Kang
authors: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
authors: Young Il
authors: YI
authors: Yeom
authors: Hematology and Oncology Sections, Department of Internal Medicine, University of Ulsan, College of Medicine, Asan Medical Center, Seoul, Korea.
authors: Jae-Lyun
authors: JL
authors: Lee
authors: Hematology and Oncology Sections, Department of Internal Medicine, University of Ulsan, College of Medicine, Asan Medical Center, Seoul, Korea.
authors: Dae-Young
authors: DY
authors: Kim
authors: Hematology and Oncology Sections, Department of Internal Medicine, University of Ulsan, College of Medicine, Asan Medical Center, Seoul, Korea.
authors: Young-Shin
authors: YS
authors: Lee
authors: Hematology and Oncology Sections, Department of Internal Medicine, University of Ulsan, College of Medicine, Asan Medical Center, Seoul, Korea.
authors: Young-Ah
authors: YA
authors: Kang
authors: Hematology and Oncology Sections, Department of Internal Medicine, University of Ulsan, College of Medicine, Asan Medical Center, Seoul, Korea.
authors: Mijin
authors: M
authors: Jeon
authors: Hematology and Oncology Sections, Department of Internal Medicine, University of Ulsan, College of Medicine, Asan Medical Center, Seoul, Korea.
authors: Miee
authors: M
authors: Seol
authors: Hematology and Oncology Sections, Department of Internal Medicine, University of Ulsan, College of Medicine, Asan Medical Center, Seoul, Korea.
authors: Jung-Hee
authors: JH
authors: Lee
authors: Hematology and Oncology Sections, Department of Internal Medicine, University of Ulsan, College of Medicine, Asan Medical Center, Seoul, Korea.
authors: Je-Hwan
authors: JH
authors: Lee
authors: Department of Clinical Epidemiology and Biostatistics, University of Ulsan, College of Medicine, Asan Medical Center, Seoul, Korea.
authors: Hwa Jung
authors: HJ
authors: Kim
authors: Department of Clinical Epidemiology and Biostatistics, University of Ulsan, College of Medicine, Asan Medical Center, Seoul, Korea.
authors: Sung-Cheol
authors: SC
authors: Yun
authors: Hematology and Oncology Sections, Department of Internal Medicine, University of Ulsan, College of Medicine, Asan Medical Center, Seoul, Korea. Electronic address: khlee2@amc.seoul.kr.
authors: Kyoo-Hyung
authors: KH
authors: Lee
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000961:Antilymphocyte Serum / Q000627:therapeutic use; D002066:Busulfan / Q000627:therapeutic use; D002648:Child; D018450:Disease Progression; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000401:mortality / Q000473:pathology; D019337:Hematologic Neoplasms / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006650:Histocompatibility Testing; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000637:transplantation*; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D019653:Myeloablative Agonists / Q000627:therapeutic use*; D012189:Retrospective Studies; D016019:Survival Analysis; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D000961:Antilymphocyte Serum; D019653:Myeloablative Agonists; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine
keywords: Donor natural killer cell infusion; Human leukocyte antigen–haploidentical hematopoietic cell transplantation