肿瘤细胞治疗研究
英文原题：An Open-Label, Phase I Clinical Trial of Super CAR-T With GPC3-Positive Advanced Hepatocellular Carcinoma
这是一项 I 期注册临床试验，评估 CAR-T 细胞治疗肝细胞癌的安全性、可行性及初步疗效。当前状态：招募中。计划入组 15 例。试验地点：中国 · 广州（共 1 个中心，其中中国 1 个）。登记号：NCT07493044。
不限性别 · ≥ 18 Years 且 ≤ 75 Years
纳入标准： 1. 受试者理解并自愿签署知情同意书后，方可参加任何试验相关活动； 2. 年龄18–75岁，性别不限； 3. 经组织病理学或细胞学确诊肝细胞癌（HCC）：按中国国家肝癌分期（CNLC）为不可手术IIa、IIb、IIIa或IIIb期，或按巴塞罗那肝癌临床分期（BCLC）为C期，或为不可手术/不适合局部治疗的B期；Child-Pugh肝功能评分≤7； 4. 至少2线标准全身治疗失败或不耐受； 5. 提供过去2年内采集且符合要求的肿瘤样本/活检标本，免疫组化证实GPC3表达阳性； 6. 按RECIST 1.1标准至少有一个可测量病灶； 7. ECOG体能状态评分0–1分； 8. 预期生存期>3个月； 9. 超声心动图显示左心室射血分数（LVEF）≥50%； 10. 实验室检查至少符合：ANC≥1.0×10⁹/L；血小板≥75×10⁹/L；血红蛋白≥75 g/L；肌酐清除率≥60 mL/min；AST≤5×ULN；ALT≤5×ULN；总胆红素≤3×ULN； 11. HBsAg或HBcAb阳性者，HBV-DNA须≤2000 IU/mL； 12. 有生育能力的女性在接受研究治疗前妊娠检测须为阴性，并同意治疗期间采取有效避孕措施。 排除标准： 1. 单采前2周内接受过大手术，或预计试验期间需要接受大手术； 2. 对本研究使用的任何药物成分过敏，包括但不限于环磷酰胺、氟达拉滨、CAR-T产品或其辅料； 3. 既往手术或治疗相关不良反应尚未恢复至≤2级；脱发、色素沉着及研究者认为不影响耐受性的其他情况除外； 4. 有临床意义的中枢神经系统疾病（如癫痫、严重脑血管狭窄）或其他伴明显神经系统症状的疾病（包括精神障碍）； 5. 单采前2周内因本研究疾病接受放疗、全身化疗或免疫检查点抑制剂；或单采前1周内接受索拉非尼、瑞戈非尼、仑伐替尼等小分子靶向治疗； 6. 血浆单采前7天内接受全身性糖皮质激素治疗；目前或近期使用吸入/局部糖皮质激素，以及接受生理剂量替代治疗者可入组； 7. 任何未控制的活动性感染，包括活动性结核或需要全身治疗的感染性疾病； 8. 已知活动性自身免疫性疾病，包括但不限于类风湿关节炎、系统性红斑狼疮、自身免疫性肝炎、多发性硬化和肾小球肾炎；白癜风患者不排除； 9. 有器官移植、自体/异基因干细胞移植或肾脏替代治疗史； 10. HCV抗体阳性且HCV RNA高于检测下限；HIV抗体阳性；梅毒抗体阳性； 11. 目前妊娠或哺乳，或计划在研究期间妊娠； 12. 研究者认为无法或不愿遵守研究方案要求。
Inclusion Criteria:
1. Understand and voluntarily sign the informed consent form prior to participating in any trial-related activities;
2. Be between 18 and 75 years of age; gender is not restricted;
3. Diagnosed with hepatocellular carcinoma (HCC) based on histopathological or cytological examination: Patients classified as inoperable Stage IIa, IIb, IIIa, or IIIb according to the Chinese National Liver Cancer (CNLC) staging system, or Stage C according to the Barcelona Clinic Liver Cancer (BCLC) staging system, or Stage B patients who are inoperable or unsuitable for local treatment; Child-Pugh liver function score ≤ 7;
4. Previous failure of or intolerance to at least two lines of standard systemic therapy;
5. The subject must provide a tumor sample or biopsy specimen collected within the past 2 years that meets the requirements and tests positive for GPC3 expression via immunohistochemistry;
6. At least one measurable lesion according to RECIST 1.1 criteria;
7. ECOG performance status of 0-1;
8. Expected survival of more than 3 months;
9. Echocardiography showing a left ventricular ejection fraction (LVEF) ≥50%;
10. Laboratory test results must meet at least the following criteria:
ANC ≥1.0×10⁹/L; PLT ≥75×10⁹/L; Hb ≥ 75 g/L; Creatinine clearance ≥ 60 mL/min; AST ≤ 5×ULN; ALT≤ 5×ULN; TBIL ≤ 3×ULN;
11. If HBsAg-positive or HBcAb-positive, HBV-DNA must be ≤ 2000 IU/mL;
12. Women of childbearing potential must have a negative pregnancy test prior to receiving study treatment; they must agree to use effective contraception during treatment.
Exclusion Criteria:
1. The subject has undergone major surgery within 2 weeks prior to apheresis, or is expected to undergo major surgery during the trial;
2. The subject is allergic to any component of the drugs to be used in this study, including but not limited to cyclophosphamide, fludarabine, CAR-T products, or their excipients;
3. Has not recovered from adverse reactions related to prior surgery or treatment to Grade ≤ 2; exceptions include alopecia, hyperpigmentation, and other conditions deemed by the investigator not to affect the subject's tolerability;
4. Has a clinically significant central nervous system (CNS) disorder (e.g., epilepsy, severe cerebrovascular stenosis) or other diseases presenting with significant neurological symptoms (including psychiatric disorders);
5. Received radiotherapy, systemic chemotherapy, or immune checkpoint inhibitors for the study disease within 2 weeks prior to apheresis; or received small-molecule targeted therapies such as sorafenib, regorafenib, or lenvatinib within 1 week prior to apheresis;
6. Received systemic glucocorticoid therapy within 7 days prior to single-plasma donation; patients currently using or who have recently used inhaled or topical glucocorticoids, as well as those on physiological-dose replacement therapy, are eligible for enrollment;
7. Any uncontrolled active infection, including but not limited to active tuberculosis or infectious diseases requiring systemic treatment;
8. Known active autoimmune diseases, including but not limited to rheumatoid arthritis, systemic lupus erythematosus, autoimmune hepatitis, multiple sclerosis, and glomerulonephritis (patients with vitiligo are not excluded);
9. History of organ transplantation, autologous/allogeneic stem cell transplantation, or renal replacement therapy;
10. HCV antibody-positive with HCV RNA levels above the lower limit of detection; HIV antibody-positive; syphilis antibody-positive;
11. Currently pregnant or breastfeeding, or planning to become pregnant during the study;
12. Participants deemed by the investigator to be unable or unwilling to comply with the requirements of the study protocol.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：Dose Limiting Toxicity (DLT) · Determining the DLT of Super CAR-T adoptive Immunotherapy. · 28 days after cell infusion；Maximum Tolerated Dose (MTD) · Determining the MTD of Super CAR-T adoptive Immunotherapy. · 28 days after cell infusion
次要终点：Objective Response Rate(ORR)；Progression Free Survival(PFS)；Overall Survival (OS)
按阳性细胞剂量递增方案进行Super CAR-T毒性剂量递增测试，设置1、2、3级剂量。
这是一项单中心、开放标签、采用3+3剂量递增设计的I期临床试验，评估Super CAR-T治疗GPC3阳性晚期肝细胞癌的安全性和耐受性。
This study was a phase I safety and tolerability clinical trial conducted in a single-center, open-label, 3+3 design with dose escalation.
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