肿瘤细胞治疗研究
英文原题：Dual-target CD70/CAIX CAR-NK Cells for Advanced Clear Cell Renal Cell Carcinoma
这是一项 I/II 期注册临床试验，评估细胞治疗用于肾细胞癌的安全性、可行性及初步疗效。当前状态：招募中。计划入组 36 例。试验地点：中国 · 深圳（共 1 个中心，其中中国 1 个）。登记号：NCT07551349。
不限性别 · ≥ 18 Years
纳入标准： • 签署书面知情同意书，并愿意遵守方案流程。 • 签署知情同意书时年龄≥18岁。 • 组织学确诊为不可切除或转移性透明细胞RCC，或含透明细胞成分的RCC，且影像学显示标准治疗后疾病进展。 • 既往至少接受过一种以PD-1/PD-L1为基础的治疗方案及一种VEGF通路靶向方案；或有记录证明不耐受／不适合现有标准系统治疗。 • 根据RECIST 1.1至少有1个可测量病灶。 • 有可用的存档肿瘤组织，或愿意接受新鲜活检以进行中心生物标志物检测；须符合方案规定的CD70和／或CAIX肿瘤阳性标准。生物标志物扩展部分优先纳入双阳性病例。 • ECOG体能状态评分0～1分。 • 骨髓、肝、心、肺、肾功能符合方案规定（例如ANC、血小板、胆红素、AST/ALT、肌酐清除率、血氧饱和度和心室功能均达到方案阈值）。 • 预期生存期至少12周。 • 有生育能力者妊娠试验阴性，并同意在方案规定的风险期内采取高效避孕措施。 • 既往治疗过的脑转移如临床稳定，且淋巴细胞清除前至少14天未增加糖皮质激素剂量，可允许入组。 排除标准： • 存在活动性、未治疗或有症状的中枢神经系统转移、软脑膜疾病或未控制的癫痫。 • 方案规定洗脱期内接受过基因修饰细胞治疗（包括既往CAR-T、CAR-NK、CAR-NKT或TCR工程化治疗）。 • 既往接受过异基因干细胞移植，或接受过需持续显著免疫抑制治疗的实体器官移植。 • 患有需要全身免疫抑制治疗的活动性自身免疫性疾病；允许生理替代剂量。 • 存在未控制的活动性感染，包括未控制的乙肝、丙肝、HIV、结核或脓毒症。 • 存在可能增加CAIX靶向治疗风险的有临床意义肝胆疾病，如活动性胆管炎、原发性硬化性胆管炎、胆道梗阻、Child-Pugh B/C级肝硬化或既往肝静脉闭塞病。 • 存在有临床意义的心血管疾病（如不稳定型心绞痛、近期心肌梗死、未控制的心律失常或有临床意义的心力衰竭）。 • 淋巴细胞清除前7天内使用泼尼松等效剂量>10 mg/日的全身性糖皮质激素；生理替代治疗除外。 • 妊娠或哺乳期。 • 另有需要全身治疗的活动性浸润性恶性肿瘤；方案规定的低风险例外情况除外。 • 已知对氟达拉滨、环磷酰胺或关键研究产品辅料过敏。
Inclusion Criteria: * Written informed consent and willingness to comply with protocol procedures. * Age \>= 18 years at the time of consent. * Histologically confirmed unresectable or metastatic clear cell RCC, or RCC with a clear-cell component, with radiographic progression after standard therapy. * Prior exposure to at least one PD-1 / PD-L1-based regimen and at least one VEGF-pathway targeted regimen, or documented intolerance / unsuitability for available standard systemic options. * At least one measurable lesion by RECIST 1.1. * Available archival tumor tissue or willingness to undergo fresh biopsy for central biomarker testing; protocoldefined tumor positivity for CD70 and/or CAIX is required. Dual-positive cases are preferred for the biomarkerexpansion portion. * ECOG performance status 0-1. * Adequate marrow, liver, cardiac, pulmonary, and renal function as defined by the protocol (for example, ANC, platelets, bilirubin, AST/ALT, creatinine clearance, oxygen saturation, and left ventricular function within protocoldefined limits). * Life expectancy of at least 12 weeks. * Negative pregnancy test for participants of childbearing potential and agreement to highly effective contraception during protocol-defined risk windows. * Previously treated brain metastases are allowed if clinically stable and off escalating corticosteroids for at least 14 days before lymphodepletion. Exclusion Criteria: * Active, untreated, or symptomatic central nervous system metastases, leptomeningeal disease, or uncontrolled seizure disorder. * Prior gene-modified cellular therapy (including prior CAR-T, CAR-NK, CAR-NKT, or TCR-engineered therapy) within the protocol-defined washout window. * Prior allogeneic stem cell transplant or solid organ transplant with ongoing clinically significant immunosuppression. * Active autoimmune disease requiring systemic immunosuppressive treatment; physiologic replacement doses are permitted. * Active uncontrolled infection, including uncontrolled hepatitis B, hepatitis C, HIV, tuberculosis, or sepsis. * Clinically significant hepatobiliary disease that could increase risk from CAIX-directed therapy, such as active cholangitis, primary sclerosing cholangitis, biliary obstruction, Child-Pugh B/C cirrhosis, or prior hepatic venoocclusive disease. * Clinically significant cardiovascular disease (for example, unstable angina, recent myocardial infarction, uncontrolled arrhythmia, or clinically meaningful heart failure). * Systemic corticosteroid use greater than 10 mg prednisone equivalent daily within 7 days before lymphodepletion, unless required as physiologic replacement. * Pregnancy or breastfeeding. * Another active invasive malignancy requiring systemic treatment, except for protocol-defined low-risk exceptions. * Known hypersensitivity to fludarabine, cyclophosphamide, or a critical study-product excipient.
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 toxicities (DLTs) · Incidence of dose-limiting toxicities (DLTs) during the DLT window, graded by CTCAE v5.0 · 28 Days；Determination of recommended phase 2 dose · 8 weeks
次要终点：Objective response rate (ORR) per RECIST 1.1 by independent radiologic review；Overall Survival (OS)
这项Ⅰ/Ⅱ期研究评估异基因双靶点CD70/CAIX CAR-NK细胞在氟达拉滨／环磷酰胺淋巴细胞清除后用于标准治疗后进展的晚期或转移性透明细胞肾细胞癌（RCC）成人患者的安全性、可行性和初步抗肿瘤活性。研究将确定推荐剂量和给药方案，描述肝胆安全性，并探索CD70高表达、CAIX高表达或双高表达肿瘤是否获益最大。生物标志物定义的活性信号将用于指导后续开发优先选择CD70、CAIX/CA9或继续采用双靶点策略。
Phase 1/2 study evaluates the safety, feasibility, and preliminary antitumor activity of allogeneic dual-target CD70/CAIX CAR-NK cells after fludarabine/cyclophosphamide lymphodepletion in adults with advanced or metastatic clear cell RCC that has progressed after standard therapy. The study is designed to determine a recommended dose and schedule, characterize hepatobiliary safety, and explore whether CD70-high, CAIX-high, or dual-high tumors derive the greatest benefit. Biomarker-defined activity signals will be used to guide whether later development should prioritize CD70, CAIX/CA9, or continued dual-targeting.
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