肿瘤细胞治疗研究
英文原题：Dual-Target CAR-NK Cells for Advanced Breast Cancer HER2+ TNBC
这是一项 I/II 期注册临床试验，评估 NK 细胞治疗乳腺癌的安全性、可行性及初步疗效。当前状态：招募中。计划入组 60 例。试验地点：中国 · 深圳（共 1 个中心，其中中国 1 个）。登记号：NCT07510802。
不限性别 · ≥ 18 Years 且 ≤ 75 Years
纳入标准： * 经组织学确诊的乳腺癌，为局部晚期、不可切除或转移性。 * 疾病亚型：HER2阳性乳腺癌或三阴性乳腺癌（TNBC）。 * 在适合该疾病亚型和治疗线的标准治疗后出现进展、不耐受或不适合接受标准治疗。 * 根据RECIST v1.1至少有一个可测量病灶。 * 可获得肿瘤抗原评估（新鲜或存档样本）：至少一种候选靶抗原（HER2/ERBB2、MUC1或ROR1）的表达。对于TNBC，可进行间皮素评估用于探索性分析。 * ECOG体能状态评分0-1。 * 器官功能充分（示例阈值）：ANC ≥ 1.0 x 10^9/L；血小板 ≥ 75 x 10^9/L；血红蛋白 * 8 g/dL；AST/ALT ≤ 3倍ULN（伴肝转移时≤ 5倍ULN）；总胆红素 ≤ 1.5倍ULN；肌酐清除率 * 50 mL/min。 * 左心室射血分数（LVEF）≥ 45%，且无未控制的心律失常。 * 有生育能力的受试者妊娠试验阴性；同意在研究治疗期间及末次CAR-NK输注后6个月内使用有效避孕措施。 * 能够理解并愿意签署知情同意书。 排除标准： * 活动性、未经治疗的中枢神经系统（CNS）转移或软脑膜疾病。经治疗的CNS转移患者若临床稳定≥ 4周且未使用高剂量类固醇，可能符合条件。 * 6个月内接受过既往基因修饰细胞治疗（如CAR-T或CAR-NK），或既往细胞治疗遗留未缓解的≥ 2级毒性。 * 需要全身免疫抑制治疗的临床显著活动性自身免疫性疾病（允许生理性类固醇替代治疗）。 * 未控制的感染，包括未控制的HBV、HCV或HIV感染（根据研究者判断，控制良好的感染可能符合条件）。 * 对氟达拉滨或环磷酰胺有严重过敏史。 * 妊娠或哺乳期。 * 同时参加可能混淆安全性或疗效评估的另一项干预性研究。 * 研究者判断的任何会使受试者不适合参加研究的情况（如未控制的合并症、无法遵守方案程序）。
Inclusion Criteria: * Histologically confirmed breast carcinoma that is locally advanced, unresectable, or metastatic. * Disease subtype: HER2-positive breast cancer or triple-negative breast cancer (TNBC). * Progression after, intolerance to, or ineligibility for standard therapies appropriate for the disease subtype and line of therapy. * At least one measurable lesion per RECIST v1.1. * Tumor antigen assessment available (fresh or archival): expression of at least one candidate target antigen (HER2/ERBB2, MUC1, or ROR1). For TNBC, mesothelin assessment may be performed for exploratory analyses. * ECOG performance status 0-1. * Adequate organ function (example thresholds): ANC ≥ 1.0 x 10\^9/L; platelets ≥ 75 x 10\^9/L; hemoglobin * 8 g/dL; AST/ALT ≤ 3x ULN (≤ 5x with liver metastases); total bilirubin ≤ 1.5x ULN; creatinine clearance * 50 mL/min. * Left ventricular ejection fraction (LVEF) ≥ 45% and no uncontrolled cardiac arrhythmia. * Negative pregnancy test for participants of childbearing potential; agreement to use effective contraception during study treatment and for 6 months after last CAR-NK infusion. * Ability to understand and willingness to sign informed consent. Exclusion Criteria: * Active, untreated central nervous system (CNS) metastases or leptomeningeal disease. Patients with treated CNS metastases may be eligible if clinically stable for ≥ 4 weeks and off high-dose steroids. * Prior gene-modified cellular therapy (e.g., CAR-T or CAR-NK) within 6 months or unresolved grade ≥ 2 toxicity from prior cellular therapy. * Clinically significant active autoimmune disease requiring systemic immunosuppression (physiologic steroid replacement permitted). * Uncontrolled infection, including uncontrolled HBV, HCV, or HIV infection (controlled infections may be eligible per investigator). * History of severe hypersensitivity to fludarabine or cyclophosphamide. * Pregnant or breastfeeding. * Concurrent participation in another interventional study that could confound safety or efficacy assessments. * Any condition that, in the investigator's judgment, would make the participant unsuitable for the study (e.g., uncontrolled comorbidity, inability to comply with protocol procedures).
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) · 28 days；Recommended Phase 2 Dose (RP2D) based on overall safety · 56 days
次要终点：Objective response rate (ORR) by RECIST v1.1；Disease control rate
具有可测量病灶且至少表达一种靶抗原（HER2、MUC1或ROR1）的晚期/转移性乳腺癌。受试者接受淋巴细胞清除术后，单次输注双靶点CAR-NK（根据抗原谱选择构建体）
HER2阳性乳腺癌（HER2 IHC 3+或IHC 2+且ISH扩增）伴MUC1表达；在RP2D接受HER2/MUC1双靶点CAR-NK
HER2阳性乳腺癌或HER2低表达疾病伴ROR1高表达；在RP2D接受HER2/ROR1双靶点CAR-NK。
三阴性乳腺癌伴MUC1和/或ROR1表达；在RP2D接受MUC1/ROR1双靶点CAR-NK。探索性TNBC亚队列：间皮素阳性TNBC可单独分析。
本研究旨在测试一种研究性双靶点嵌合抗原受体自然杀伤（CAR-NK）细胞疗法在晚期乳腺癌成人患者中的安全性和初步抗肿瘤活性。在进行肿瘤抗原评估（HER2/ERBB2、MUC1、ROR1，TNBC病例检测间皮素）后，每位参与者将在接受短程淋巴细胞清除性化疗后，根据其肿瘤特征接受最适合的双靶点CAR-NK产品。
This study tests the safety and preliminary anti-tumor activity of an investigational dual-target chimeric antigen receptor natural killer (CAR-NK) cell therapy in adults with advanced breast cancer. After a tumor antigen assessment (HER2/ERBB2, MUC1, ROR1,TNBC cases mesothelin), each participant will receive the most suitable dual-target CAR-NK product for their tumor profile, following short-course lymphodepleting chemotherapy.
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