肿瘤细胞治疗研究
英文原题：Dual-Target GPC3/B7-H3 CAR-NK Cells for Advanced HCC
这是一项 I/II 期注册临床试验，评估 NK 细胞治疗肝细胞癌、肝癌的安全性、可行性及初步疗效。当前状态：招募中。计划入组 30 例。试验地点：中国 · 深圳（共 1 个中心，其中中国 1 个）。登记号：NCT07500220。
不限性别 · ≥ 18 Years 且 ≤ 75 Years
纳入标准： * 年龄18–75岁； * 组织学或细胞学确诊HCC，或影像学诊断HCC且入组前必须通过组织检测确认靶点表达； * 不可切除、局部晚期或转移性HCC，不适合根治性手术、移植或进一步局部区域治疗；BCLC C期，或不适合局部区域治疗/局部治疗后进展的B期； * 至少一种既往标准全身治疗后疾病进展、不耐受或不符合治疗条件； * 中央病理检测显示免疫组化（IHC）GPC3阳性（≥25%的存活肿瘤细胞表达），且B7-H3阳性（≥10%的肿瘤细胞和/或肿瘤相关间质/血管细胞表达）； * 按RECIST 1.1至少有一个可测量病灶；肝内病灶须通过增强三期CT或MRI评估； * ECOG体能状态评分0–1分； * Child-Pugh A级，或稳定的Child-Pugh B7级且无未控制腹水或近期肝性脑病； * 预期生存期≥12周； * 器官功能充分：白细胞≥2.5×10⁹/L；血小板≥60×10⁹/L；血红蛋白≥9 g/dL；血清白蛋白≥30 g/L；肌酐清除率≥40 mL/min；AST/ALT≤5×ULN；总胆红素≤2.5×ULN；INR/凝血酶原时间符合方案规定范围； * HBsAg或anti-HBc阳性者，HBV DNA须<200 IU/mL，且淋巴清除治疗前已接受适当抗病毒治疗。符合方案规定的丙肝感染控制者可入组； * 有生育能力的受试者血清妊娠检测阴性，并同意采取有效避孕措施； * 能够理解并签署知情同意书。 排除标准： * 方案规定洗脱期内接受过基因修饰细胞治疗（如CAR-T、CAR-NK或TCR工程化治疗），或相关临床显著毒性尚未恢复； * 活动性、未控制感染，包括未控制的细菌、病毒或真菌感染、未控制的HIV、病毒载量未控制的活动性HBV/HCV或活动性结核； * 已知活动性CNS转移或软脑膜疾病，需增加类固醇剂量或紧急局部干预； * 有肝移植或其他实体器官移植史，或目前需要长期免疫抑制治疗； * 有临床意义腹水且需频繁引流；过去4周内≥2级肝性脑病；或近期有临床意义的静脉曲张/胃肠道出血； * 肿瘤广泛替代肝脏（例如≥70%），或完全阻塞主要门静脉/肝静脉且研究者认为治疗风险过高； * 在方案规定洗脱期内接受大手术、局部区域治疗、放疗或全身抗癌治疗，且距淋巴清除治疗时间不足； * 活动性自身免疫性疾病且需要全身免疫抑制治疗，或长期使用超过方案规定剂量的全身性皮质类固醇； * 有临床意义的心血管疾病（近期心肌梗死、不稳定心律失常、未控制心力衰竭）、未控制肺病，或其他显著增加研究风险的严重合并症； * 妊娠或哺乳； * 存在任何进展中或目前需全身治疗的其他活动性恶性肿瘤； * 研究者判断会影响安全性、方案依从性或结果解释的任何其他医学或精神状况。
Inclusion Criteria: * Age 18 to 75 years. * Histologically or cytologically confirmed HCC, or radiologically diagnosed HCC with mandatory tissue confirmation of target expression before enrollment. * Unresectable, locally advanced, or metastatic HCC not amenable to curative surgery, transplant, or further locoregional therapy; BCLC stage C, or stage B that is not suitable for or has progressed after locoregional therapy. * Disease progression on, intolerance to, or ineligibility for at least 1 prior standard systemic regimen. * Central pathology showing GPC3 positivity in \>=25% of viable tumor cells by IHC and B7-H3 positivity in \>=10% of tumor cells and/or tumor-associated stromal/vascular cells by IHC. * At least 1 measurable lesion by RECIST 1.1; intrahepatic lesions must be assessable by contrast-enhanced triphasic CT or MRI. * ECOG performance status 0 to 1. * Child-Pugh class A or stable Child-Pugh B7 without uncontrolled ascites or recent encephalopathy. * Estimated life expectancy \>=12 weeks. * Adequate organ function: WBC \>=2.5 x 10\^9/L; platelets \>=60 x 10\^9/L; hemoglobin \>=9 g/dL; serum albumin \>=30 g/L; creatinine clearance \>=40 mL/min; AST/ALT \<=5 x ULN; total bilirubin \<=2.5 x ULN; INR/prothrombin time within protocol-defined range. * If HBsAg positive or anti-HBc positive, HBV DNA must be \<200 IU/mL and the participant must be on appropriate antiviral therapy before lymphodepletion. Controlled HCV is allowed if per protocol. * Negative serum pregnancy test for participants of childbearing potential and agreement to effective contraception. * Ability to understand and sign informed consent. Exclusion Criteria: * Prior gene-modified cellular therapy (for example prior CAR-T, CAR-NK, or TCR-engineered therapy) within the protocol-defined washout period or with unresolved clinically significant toxicity. * Active, uncontrolled infection, including uncontrolled bacterial, viral, or fungal infection; uncontrolled HIV; active HBV or HCV with uncontrolled viral load; or active tuberculosis. * Known active CNS metastases or leptomeningeal disease requiring escalating steroids or urgent local intervention. * Liver transplant or other solid-organ transplant history, or current requirement for chronic immunosuppression. * Clinically significant ascites requiring frequent drainage, grade \>=2 hepatic encephalopathy within 4 weeks, or recent clinically significant variceal/GI bleeding. * Extensive liver replacement by tumor (for example \>=70%) or complete major portal vein/hepatic venous obstruction judged to create excessive treatment risk. * Major surgery, locoregional therapy, radiotherapy, or systemic anticancer therapy too close to lymphodepletion per protocol-defined washout period. * Active autoimmune disease requiring systemic immunosuppressive therapy, or chronic systemic corticosteroids above protocol threshold. * Clinically significant cardiovascular disease (recent myocardial infarction, unstable arrhythmia, uncontrolled heart failure), uncontrolled pulmonary disease, or other serious comorbidity that materially increases study risk. * Pregnant or breastfeeding. * Any other active malignancy that is progressing or requires current systemic treatment. * Any medical or psychiatric condition that, in the investigator's judgment, would compromise safety, protocol compliance, or interpretation of results.
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；Incidence, type, and severity of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) · 12 months
次要终点：response rate (ORR) by RECIST 1.1 and mRECIST；Disease control rate (DCR)；Duration of response (DoR)；Progression-free survival (PFS)；Overall survival (OS)
生物标志物确认阳性的晚期HCC成人患者接受氟达拉滨/环磷酰胺淋巴清除治疗，随后在I期接受指定剂量水平的异基因GPC3/B7-H3双靶点CAR-NK细胞；II期接受RP2D剂量。
这是一项开放标签研究，评估针对GPC3和B7-H3的异基因双靶点CAR-NK产品用于成人晚期肝细胞癌。研究以GPC3作为主要靶点，因为目前临床开发中GPC3是HCC细胞治疗的主要抗原；同时加入B7-H3，以降低抗原逃逸并扩大对肿瘤细胞及肿瘤微环境成分的覆盖。研究首先评估安全性和剂量限制性毒性，随后在II期推荐剂量（RP2D）下扩展入组。
open-label trial of an allogeneic dual-target CAR-NK product directed against GPC3 and B7-H3 for adults with advanced hepatocellular carcinoma. The design intentionally uses GPC3 as the primary target anchor because GPC3 is the dominant HCC cell-therapy antigen in current clinical development, while adding B7-H3 to reduce antigen escape and to broaden coverage across tumor and tumor-microenvironment compartments. The study first evaluates safety and dose-limiting toxicities, then expands at the recommended phase 2 dose.
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