肿瘤细胞治疗研究
英文原题：Infusion of Alloreactive nk Cells for Mrd-positive Aml Patients
⚠ 该试验的登记信息已有 19 个月未更新， 页面上显示的「招募中」可能已经失效。联系研究中心之前，建议先到 ClinicalTrials.gov 核对登记原文的最新状态与联系方式。
这是一项分期未标注的注册临床试验，评估 NK 细胞治疗急性髓系白血病的安全性、可行性及初步疗效。当前状态：招募中。计划入组 22 例。试验地点：欧洲 · 博洛尼亚（共 1 个中心）。登记号：NCT06885476。
不限性别 · ≥ 18 Years
纳入标准：新发或继发AML；年龄≥18岁；形态学完全缓解；适合异基因干细胞移植；诱导化疗后MRD阳性；有KIR配体不相容的单倍型供者；体能状态≥70%（Karnofsky评分）或≤2（WHO评分）；肾功能充分（血清肌酐<2 mg/dL）、肺功能充分（血氧饱和度≥96%）和肝功能充分（ALT/AST<正常值上限的2.5倍）；超声心动图测定左心室射血分数（LVEF）>50%；签署知情同意书。 排除标准：AML FAB M3型；HIV阳性；高病毒载量HCV阳性；妊娠或哺乳期女性；当前未控制的感染；有液体潴留体征或症状（如胸腔积液）。
Inclusion Criteria: * Diagnosis of de novo or secondary AML * Age ≥ 18 years * Morphologic CR * Eligibility for ASCT * MRD-positivity after induction chemotherapy * Availability of a KIR-L incompatible haploidentical donor * Performance Status ≥ 70% (Karnofsky score) or ≤ 2 (WHO). * Adequate renal (serum creatinine \< 2 mg/dl), pulmonary (Sat O2 ≥ 96%) and hepatic (ALT/AST \< 2.5 x N) function. * Left Ventricular Ejection Fraction (LVEF) of \>50% as determined by Echocardiogram (ECHO). * Signed informed consent. Exclusion Criteria: * Diagnosis of AML FAB M3 * HIV positivity. * HCV positivity with high viral load. * Pregnant or nursing females. * Current uncontrolled infection. * Signs or symptoms of fluid retention (e.g. pleural effusion).
以上为辅助阅读译文。是否适合入组须由主治医生判断，最终以登记平台与研究者确认为准。
主要终点：Safety of infusing a functional target cell dose of 2x105 alloreactive NK cells/kg in AML patients,eligible for ASCT, with persistent MRD after conventional chemotherapy · Safety of infusing a functional target cell dose of 2x105 alloreactive NK cells/kg in AML patients,eligible for ASCT, with persistent MRD after conventional (number of adverse events and severe adverse events) · 48 months；Feasibility of collecting a functional target cell dose of 2x105 alloreactive NK cells/kg in at least 70% of patients entering the study · Feasibility of collecting a functional target cell dose of 2x105 alloreactive NK cells/kg in at least 70% of patients entering the study as evaluated by in vitro cytotoxicity assay. · 48 months
次要终点：Number of patients who achieve and maintain MRD negativity after infusion of alloreactive NK cells；Number of patients who enter ASCT in MRD-negativity；Relapse-free survival (RFS) of patients infused with alloreactive NK cells；overall survival (OS) of patients infused with alloreactive NK cells；Assess the predictive impact of donor NK cell repertoire on overall survival；Assess the predictive impact of donor NK cell repertoire on relapse-free survival；Evaluate the microchimerism of patients receiving human NK cells；Functionally evaluate, in vitro and ex vivo, the antitumor activity of infused NK cells
为常规化疗后持续微小残留病阳性、符合异基因造血干细胞移植条件的急性白血病患者输注异反应性NK细胞。
这项介入性移植研究评估异反应性NK细胞输注用于成年AML患者的可行性和安全性。患者适合接受异基因造血干细胞移植，常规化疗后达到完全缓解，但仍有微小残留病（MRD）阳性。研究纳入符合条件的KIR配体不匹配单倍型供者；评估供者异反应性NK细胞库并确定用于采集的功能性细胞剂量。NK细胞从供者稳态大容量白细胞单采产物中分选；若产物中NK细胞至少为10×10^6/kg，则进行纯化。免疫磁性富集包括先去除CD3+ T细胞，再阳性选择CD56+ NK细胞。 患者接受氟达拉滨（第−5至−3天，每日25 mg/m²）和环磷酰胺（第−2天2 g/m²）免疫抑制化疗。环磷酰胺后2天（第0天）静脉输注一次冷冻保存的NK细胞，随后皮下注射IL-2（10×10^6 IU/天，每周3次，共2周、6次）。采集外周血开展生物学研究，包括微嵌合体检测、追踪供者NK细胞30天、免疫表型、NK细胞克隆和细胞毒性功能检测。输注后至少随访12个月。
This is a interventional, transplantation study. The procedure under study is the infusion of alloreactive NK cells in adult AML patients, eligible for ASCT, who achieved CR after conventional chemotherapy, but harbor MRD-positivity. Haploidentical KIR-L mismatched donors will be included if present at least one allele mismatch at a class I locus among the following ones: HLA-C alleles with Asn77-Lys80, HLA-C alleles with Ser77-Asn80, HLA-Bw4 alleles. KIR-L mismatched donor alloreactive NK cell repertoire will be evaluated in order to determine the functional cell dose to be used for NK cell collection. Phenotypical analysis of KIRs will be correlated to functional tests. NK cells will be selected from a steady-state large volume leukapheresis product from a suitable haploidentical KIR-ligand incompatible donor. NK cell purification will be performed if the donor leukapheresis product contains at least 10x106 NK cells/Kg. Immunomagnetic enrichment of NK cells will follow two subsequent steps: 1) depletion of CD3+ T cells followed by 2) positive selection of CD56+ NK cells. Patients will receive immunosuppressive chemotherapy, fludarabine (Flu) 25 mg/mq/ from day -5 to -3 and cyclophosphamide (Cy) 2 g/mq on day -2 (Flu/Cy). Two days after Cy administration, patients will be infused intravenously with a single dose of cryopreserved NK cells (day 0), which will be followed by subcutaneous administration of IL-2 (10 x 106 IU/day, 3 times weekly) for 2 weeks (6 doses total). PB samples will also be collected for biological studies. In particular, PB samples will be collected for molecular assessment of microchimerism and tracking of haploidentical NK cells for 30 days, immunophenotype studies, alloreactive NK cells cloning and functional assays (cytotoxicity). Enrolled patients will be followed up for at least 12 months after NK cell infusion.
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