Department of Pediatrics, Chungbuk National University Hospital, Cheongju, Republic of Korea.
Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
PLoS One. 2019 Dec 13;14(12):e0225998. doi: 10.1371/journal.pone.0225998. eCollection 2019.
Under the hypothesis that early natural killer cell infusion (NKI) following haploidentical stem cell transplantation (haplo-SCT) will reduce relapse in the early post-transplant period, we conducted a pilot study to evaluate the safety and feasibility of NKI following haplo-SCT in children with recurrent neuroblastoma who failed previous tandem high-dose chemotherapy and autologous SCT.
We used the high-dose 131I-metaiodobenzylguanidine and cyclophosphamide/fludarabine/anti-thymocyte globulin regimen for conditioning and infused 3 × 107/kg of ex-vivo expanded NK cells derived from a haploidentical parent donor on days 2, 9, and 16 post-transplant. Interleukin-2 was administered (1 × 106 IU/m2/day) subcutaneously to activate infused donor NK cells on days 2, 4, 6, 9, 11, 13, 16, 18, and 20 post-transplant.
Seven children received a total of 19 NKIs, and NKI-related acute toxicities were fever (n = 4) followed by chills (n = 3) and hypertension (n = 3); all toxicities were tolerable. Grade ≥II acute GVHD and chronic GVHD developed in two and five patients, respectively. Higher amount of NK cell population was detected in peripheral blood until 60 days post-transplant than that in the reference cohort. Cytomegalovirus and BK virus reactivation occurred in all patients and Epstein-Barr virus in six patients. Six patients died of relapse/progression (n = 5) or treatment-related mortality (n = 1), and one patient remained alive.
NKI following haplo-SCT was relatively safe and feasible in patients with recurrent neuroblastoma. Further studies to enhance the graft-versus-tumor effect without increasing GVHD are needed.
基于早期自然杀伤细胞输注（NKI）在单倍体造血干细胞移植（haplo-SCT）后可减少移植后早期复发的假设，我们进行了一项试点研究，以评估在复发神经母细胞瘤患儿中进行 NKI 的安全性和可行性，这些患儿在之前的双次高剂量化疗和自体 SCT 后复发。
我们使用高剂量 131I-间碘苄胍和环磷酰胺/氟达拉滨/抗胸腺细胞球蛋白方案进行预处理，并在移植后第 2、9 和 16 天输注 3×107/kg 的来自单倍体供体父母的体外扩增 NK 细胞。在移植后第 2、4、6、9、11、13、16、18 和 20 天，皮下给予白细胞介素-2（1×106IU/m2/天）以激活输注的供体 NK 细胞。
7 名儿童共接受了 19 次 NKI，NKI 相关的急性毒性包括发热（n=4），随后出现寒战（n=3）和高血压（n=3）；所有毒性均可耐受。2 例和 5 例患者分别发生≥2 级急性移植物抗宿主病和慢性移植物抗宿主病。移植后 60 天，外周血中检测到的 NK 细胞数量高于参考队列。所有患者均出现巨细胞病毒和 BK 病毒再激活，6 例患者出现 EBV 再激活。6 例患者因复发/进展（n=5）或治疗相关死亡（n=1）死亡，1 例患者仍存活。
haplo-SCT 后进行 NKI 在复发神经母细胞瘤患者中相对安全且可行。需要进一步研究以增强移植物抗肿瘤效应而不增加移植物抗宿主病。
