Division of Hematology and Oncology, Department of Pediatrics, and.
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO.
Blood. 2022 Mar 17;139(11):1670-1683. doi: 10.1182/blood.2021013972.
Pediatric and young adult (YA) patients with acute myeloid leukemia (AML) who relapse after allogeneic hematopoietic cell transplantation (HCT) have an extremely poor prognosis. Standard salvage chemotherapy and donor lymphocyte infusions (DLIs) have little curative potential. Previous studies showed that natural killer (NK) cells can be stimulated ex vivo with interleukin-12 (IL-12), -15, and -18 to generate memory-like (ML) NK cells with enhanced antileukemia responses. We treated 9 pediatric/YA patients with post-HCT relapsed AML with donor ML NK cells in a phase 1 trial. Patients received fludarabine, cytarabine, and filgrastim followed 2 weeks later by infusion of donor lymphocytes and ML NK cells from the original HCT donor. ML NK cells were successfully generated from haploidentical and matched-related and -unrelated donors. After infusion, donor-derived ML NK cells expanded and maintained an ML multidimensional mass cytometry phenotype for >3 months. Furthermore, ML NK cells exhibited persistent functional responses as evidenced by leukemia-triggered interferon-γ production. After DLI and ML NK cell adoptive transfer, 4 of 8 evaluable patients achieved complete remission at day 28. Two patients maintained a durable remission for >3 months, with 1 patient in remission for >2 years. No significant toxicity was experienced. This study demonstrates that, in a compatible post-HCT immune environment, donor ML NK cells robustly expand and persist with potent antileukemic activity in the absence of exogenous cytokines. ML NK cells in combination with DLI present a novel immunotherapy platform for AML that has relapsed after allogeneic HCT. This trial was registered at https://clinicaltrials.gov as #NCT03068819.
儿科和年轻成人（YA）患者在异基因造血细胞移植（HCT）后复发的急性髓系白血病（AML）预后极差。标准的挽救性化疗和供体淋巴细胞输注（DLIs）几乎没有治愈的潜力。先前的研究表明，自然杀伤（NK）细胞可以通过白细胞介素-12（IL-12）、-15 和-18 在体外被刺激，从而产生具有增强抗白血病反应的记忆样（ML）NK 细胞。我们在一项 1 期试验中用供体 MLNK 细胞治疗了 9 例 HCT 后复发的 AML 儿科/YA 患者。患者接受氟达拉滨、阿糖胞苷和非格司亭治疗，2 周后输注来自原始 HCT 供体的供体淋巴细胞和 MLNK 细胞。MLNK 细胞可成功从半相合和匹配相关及不相关供体中生成。输注后，供体来源的 MLNK 细胞扩增并保持 ML 多维质谱细胞术表型>3 个月。此外，MLNK 细胞表现出持续的功能反应，表现为白血病触发的干扰素-γ产生。在 DLI 和 MLNK 细胞过继转移后，8 例可评估患者中有 4 例在第 28 天达到完全缓解。2 例患者持续缓解>3 个月，其中 1 例缓解>2 年。未发生明显毒性。这项研究表明，在相容的 HCT 后免疫环境中，供体 MLNK 细胞在没有外源性细胞因子的情况下可强有力地扩增和持续存在，并具有强大的抗白血病活性。MLNK 细胞与 DLI 联合应用为 AML 提供了一种新的免疫治疗平台，该平台在异基因 HCT 后复发。该试验在 https://clinicaltrials.gov 注册，编号为 #NCT03068819。
