肿瘤细胞治疗研究
英文原题：Cell Therapy with Anti-CD19 CAR-NK Cells in Patients with Relapsed or Resistant B-ALL
⚠ 该试验的登记信息已有 24 个月未更新， 页面上显示的「尚未开始招募」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 I/II 期注册临床试验，评估抗 CD19NK 细胞治疗白血病的安全性、可行性及初步疗效。当前状态：尚未开始招募。计划入组 10 例。试验地点：其他 · 大不里士（共 1 个中心）。登记号：NCT06631040。
不限性别 · ≥ 3 Years · 接受健康志愿者
入选标准 适用疾病：CD19阳性急性淋巴细胞白血病（ALL）。年龄≥3岁，预期生存期>12周。ECOG体能状态评分0至2分，或Karnofsky体能状态（KPS）评分>60。 有生育能力女性妊娠试验须为阴性；所有受试者均须同意自CAR-NK细胞末次输注后继续使用有效避孕措施至多2周。 骨髓、肝及肾功能符合以下实验室要求：白细胞计数（WBC）≥2500/mL；血小板≥50×10^9/L；血红蛋白（Hb）≥9.0 g/dL；淋巴细胞计数（LY）≥0.7×10^9/L且LY占比≥15%；白蛋白（Alb）≥2.8 g/dL；血清脂肪酶和淀粉酶<1.5×正常值上限；血清肌酐≤2.5 mg/dL；AST和ALT≤5×正常值上限；血清总胆红素≤2.0 mg/dL。上述检查须在登记前7天内完成。 能够提供知情同意。 排除标准 妊娠或哺乳期女性不得参加。筛查时存在活动性HIV、乙肝病毒（HBV）或丙肝病毒（HCV）感染者排除。 存在严重疾病或医疗状况，导致无法按方案管理者排除，包括活动性未控制感染、重大心血管疾病、凝血障碍、呼吸系统或免疫系统疾病、心肌梗死、心律失常、阻塞性/限制性肺病，以及精神或情绪障碍。 对包括环磷酰胺、氟达拉滨或阿地白介素在内的任何药物有严重速发型超敏反应史。 正在全身使用类固醇。近期或当前吸入类固醇不构成排除条件。 存在不稳定或活动性溃疡、胃肠道出血；需要抗凝治疗（如华法林或肝素）；或需要长期抗血小板治疗（阿司匹林剂量>300 mg/日，或氯吡格雷剂量>75 mg/日）。 白细胞单采前3个月内接受过氟达拉滨或克拉屈滨化疗。
Inclusion Criteria: Eligible diseases: Acute lymphocytic leukemia (ALL CD19+). Patients 3 years of age or older, and must have a life expectancy \> 12 weeks. Eastern cooperative oncology group (ECOG) performance status of 0-2 or karnofsky performance status (KPS) score is higher than 60. Females of child-bearing potential must have a negative pregnancy test and all subjects must agree to use an effective method of contraception for up to two weeks after the last infusion of CAR NK cells. Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements: White blood cell count (WBC) ≥ 2500c/ml, Platelets ≥ 50×10\^9/L, Hb ≥ 9.0g/dL, lymphocyte (LY) ≥ 0.7×10\^9/L, LY% ≥ 15%, Alb ≥ 2.8g/dL, serum lipase and amylase \< 1.5×upper limit of normal, serum creatinine ≤ 2.5mg/dL, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5×upper limit of normal, serum total bilirubin ≤ 2.0mg/dL. These tests must be conducted within 7 days prior to registration. Ability to give informed consent. Exclusion Criteria: Pregnant or nursing women may not participate. Active HIV, hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at the time of screening. Serious illness or medical condition which would not permit the patient to be managed according to the protocol, including active uncontrolled infection, major cardiovascular, coagulation disorders, respiratory or immune system, myocardial infarction, cardiac arrhythmias, obstructive/restrictive pulmonary disease, or psychiatric or emotional disorders. History of severe immediate hypersensitivity to any of the agents including cyclophosphamide, fludarabine, or aldesleukin. Concurrent use of systemic steroids. Recent or current use of inhaled steroids is not exclusionary. The existence of unstable or active ulcers or gastrointestinal bleeding. Patients need anticoagulant therapy (such as warfarin or heparin). Patients need long-term antiplatelet therapy (aspirin at a dose \> 300mg/d; clopidogrel at a dose \> 75mg/d). Patients using fludarabine or cladribine chemotherapy within 3 months prior to leukapheresis.
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：Incidence of dose-limiting toxicity (DLTs) · Incidence of dose-limiting toxicity (DLTs) within 4 weeks after infusion, characterized by \>= Grade 3 signs/symptoms according to CTCAE v4.03, to assess safety and tolerability. · 4 weeks；Assessment of Maximum Tolerated Dose (MTD) · 4 weeks；Overall Remission Rate (ORR) · Overall Remission Rate (ORR) two months after infusion, assessed using International lymphoma party (LWP) Group · 8 weeks
次要终点：Progression-free survival (PFS)；Duration of Response (DOR)
免疫治疗在血液系统恶性肿瘤（包括难治性B细胞急性淋巴细胞白血病〔B-ALL〕）治疗中显示出前景。一种治疗方式是CAR-NK细胞疗法，即对自然杀伤（NK）细胞进行基因改造，使其识别特定癌症抗原。与CAR-T疗法相比，CAR-NK疗法可能具有免疫反应较少、生产时间和成本较低等优势，但其抗肿瘤疗效及肿瘤微环境仍带来挑战。临床前及早期临床研究已尝试使用靶向CD19等抗原的CAR-NK细胞治疗难治性B-ALL。为进一步研究抗CD19 CAR-NK细胞疗法的潜力，本研究拟评估其安全性，并确定标准治疗无应答患者中的最大耐受剂量（MTD）。
Immunotherapy has shown promise in treating hematological malignancies, including resistant B-ALL. One approach is CAR-NK cell therapy, which involves genetically modifying natural killer (NK) cells to target specific cancer antigens. While CAR-NK therapy offers advantages over CAR-T therapy, such as reduced immune system reactions and lower production time and cost, challenges remain regarding antitumor efficacy and the tumor microenvironment. Preclinical and early clinical studies have targeted various antigens, including CD19, with CAR-NK cells in resistant B-ALL. To further investigate the potential of anti-CD19 CAR-NK cell therapy, this study aims to evaluate its safety and determine the maximum tolerated dose (MTD) in patients who have not responded to standard treatment.
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