Donor-Derived Natural Killer Cells Infused after Human Leukocyte Antigen-Haploidentical Hematopoietic Cell Transplantation: A Dose-Escalation Study
Donor-Derived Natural Killer Cells Infused after Human Leukocyte Antigen-Haploidentical Hematopoietic Cell Transplantation: A Dose-Escalation Study
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DOI：
10.1016/j.bbmt.2014.01.031
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发表时间：
2014-05-01
影响因子：
4.3
通讯作者：
Lee, Kyoo-Hyung
中科院分区：
文献类型：
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作者：
Choi, Inpyo;Yoon, Suk Ran;Lee, Kyoo-Hyung
在人类白细胞抗原（HLA）-半相合造血细胞移植（HCT）后，可以安全给予的供体来源的自然杀伤（NK）细胞的剂量仍有待确定。41例恶性血液病患者（年龄17 ~ 75岁）在接受含白消安、氟达拉滨和抗胸腺细胞球蛋白的低强度预处理后接受HLA半相合HCT。细胞捐献者（7至62岁）接受生长因子动员的白细胞分离术3至4天。在前2至3天收集的细胞用于MCI，而在最后一天收集的细胞是CD 3耗尽的，并使用人白介素-15和-21培养成NK细胞。然后在HCT后2周和3周将这些NK细胞以0.2 × 10（8）个细胞/kg体重（3例患者）、0.5 × 10（8）个细胞/kg（3例患者）、1.0 × 10（8）个细胞/kg（8例患者）和>= 1.0 × 10（8）个细胞/kg或可用细胞（27例患者）的递增剂量输注到患者体内两次。在所有剂量水平下，NK细胞输注后均未观察到急性毒性。在HLA半相合HCT和随后的供体NK细胞输注后，当参考31例在相同的预处理方案后接受HLA半相合HCT但未接受高剂量NK细胞输注的历史患者时，主要HCT结局（包括植入）的累积发生率无显著差异（绝对中性粒细胞计数≥ 500/μ L，85%对87%），2 - 4级急性移植物抗宿主病（GVHD，17%对16%），中度至重度慢性GVHD（15%对10%），和移植相关死亡率（27%对19%）。然而，白血病进展显著减少（74%至46%），移植后NK细胞输注是白血病进展较少的独立预测因素（风险比，.527）。我们的研究结果表明，当HLA半相合HCT后2至3周给予供体来源的NK细胞时，中位总剂量为2.0 × 10（8）个细胞/kg时耐受性良好。此外，它们可能会减少急性白血病的移植后进展。(c)2014年美国血液和骨髓移植协会。
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 cbntaining 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 MCI, 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 x 10(8) cells/kg of body weight (3 patients), .5 x 10(8) cells/kg (3 patients), 1.0 x 10(8) cells/kg (8 patients), and >= 1.0 x 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/mu L, 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 x 10(8) cells/kg. In addition, they may decrease post-transplantation progression of acute leukemia. (c) 2014 American Society for Blood and Marrow Transplantation.