肿瘤细胞治疗研究
英文原题：Dual-Target CAR-NK Cells for Advanced Breast Cancer (HER2+ and 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：NCT07486089。
不限性别 · ≥ 18 Years 且 ≤ 75 Years
纳入标准：组织学确诊为局部晚期、不可切除或转移性乳腺癌；HER2阳性或三阴性乳腺癌（TNBC）；针对疾病亚型和治疗线数的标准治疗后进展、不能耐受或不适合治疗；按RECIST v1.1至少有一个可测量病灶；有肿瘤抗原检测结果（新鲜或存档组织），至少表达一种候选靶点（HER2/ERBB2、MUC1、ROR1），TNBC可探索性检测间皮素；ECOG 0–1；器官功能充分（示例阈值：ANC≥1.0×10⁹/L、血小板≥75×10⁹/L、血红蛋白≥8 g/dL、AST/ALT≤ULN的3倍，肝转移时≤5倍、总胆红素≤ULN的1.5倍、肌酐清除率≥50 mL/min）；LVEF≥45%且无未控制的心律失常；有生育能力者妊娠试验阴性，并同意治疗期间及末次CAR-NK输注后6个月避孕；能够理解并签署知情同意。 排除标准：活动性、未治疗的CNS转移或软脑膜病；已治疗CNS转移者若临床稳定≥4周且未使用大剂量激素，可能符合条件；6个月内接受基因修饰细胞治疗（如CAR-T或CAR-NK），或既往细胞治疗相关≥2级毒性未缓解；需全身免疫抑制治疗的有临床意义活动性自身免疫病（生理性激素替代治疗除外）；未控制感染，包括未控制HBV、HCV或HIV（研究者可判定受控感染者是否符合条件）；对氟达拉滨或环磷酰胺严重超敏反应史；妊娠或哺乳；同时参加可能干扰安全性/疗效评估的其他干预性研究；或研究者认为不适合参加的情况（如未控制的合并症、不能遵从研究流程）。
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) · Incidence of dose-limiting toxicities (DLTs) (including cytokine release syndrome and neurotoxicity) graded by CTCAE v5.0 and ASTCT consensus criteria for CRS/ICANS · 28 Days；Safety profile · Safety profile by type, frequency, severity, and relatedness of treatment-emergent adverse events (AEs) and serious AEs. · 12 months；Recommended Phase 2 Dose · Recommended Phase 2 Dose (RP2D) based on DLTs, overall safety, and biologic activity (CAR-NK expansion/persistence). · 56 days
次要终点：Objective response rate (ORR) by RECIST v1.1 (and iRECIST, if immunotherapy response patterns are suspected).；Disease control rate (DCR)；Duration of response (DoR).；Progression-free survival (PFS)；Overall survival (OS)
适用于有可测量病灶且至少表达HER2、MUC1或ROR1一种靶抗原的晚期/转移性乳腺癌患者。接受淋巴细胞清除后，单次输注按抗原谱选择的双靶点CAR-NK。
适用于HER2阳性（IHC 3+，或IHC 2+且ISH扩增）并表达MUC1的乳腺癌；按RP2D接受HER2/MUC1双靶点CAR-NK。
适用于HER2阳性或HER2低表达且ROR1高表达乳腺癌；按RP2D接受HER2/ROR1双靶点CAR-NK。
适用于表达MUC1和/或ROR1的TNBC；按RP2D接受MUC1/ROR1双靶点CAR-NK。间皮素阳性TNBC可纳入探索性亚组单独分析。
本研究测试试验性双靶点嵌合抗原受体自然杀伤（CAR-NK）细胞治疗晚期乳腺癌成人患者的安全性和初步抗肿瘤活性。检测肿瘤抗原HER2/ERBB2、MUC1、ROR1，并在部分三阴性乳腺癌病例中检测间皮素；随后按肿瘤抗原表达谱给予最匹配的双靶点CAR-NK细胞，给药前接受短疗程淋巴细胞清除化疗。
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, and in some 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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