肿瘤细胞治疗研究
英文原题：Efficacy and Safety of MSLN CAR-T in Advanced Malignant Tumors
这是一项 I/II 期注册临床试验，评估 CAR-T 细胞治疗相关疾病的安全性、可行性及初步疗效。当前状态：招募中。计划入组 20 例。试验地点：中国 · 深圳（共 1 个中心，其中中国 1 个）。登记号：NCT07399769。
不限性别 · ≥ 18 Years 且 ≤ 75 Years
纳入标准：
1. 年龄18-75岁（≥18且≤75岁），性别不限；
2. 受试者自愿参加研究，并由受试者或其法定授权代表签署书面知情同意书；
3. 经组织病理学确诊的不可切除、局部晚期、复发或转移性实体恶性肿瘤；根据AJCC TNM分期系统（第8版，2017年），诊断为III期或IV期实体恶性肿瘤的受试者；
4. 根据RECIST v1.1存在可测量和可评估的病灶；
5. 经免疫组织化学（IHC）证实肿瘤组织中MSLN表达阳性；
6. 受试者必须已接受标准一线治疗，且出现疾病进展或对该治疗不耐受；
7. 受试者不适合根治性放化疗和/或手术/免疫检查点抑制剂等治愈性治疗方式，或拒绝手术切除；
8. 细胞治疗前2周内未接受过抗体类治疗；
9. ECOG体能状态评分0-2；
10. 无外周血白细胞采集禁忌症；
11. 预计生存期≥ 3个月。
排除标准：
1. 对细胞产品任何成分有过敏史；
2. 全血细胞计数（CBC）存在以下任何血液学异常：WBC ≤ 1 × 10^9/L，中性粒细胞绝对计数（ANC）≤ 0.5 × 10^9/L，淋巴细胞绝对计数（ALC）≤ 0.5 × 10^9/L，或血小板（PLT）≤ 25 × 10^9/L；
3. 存在以下任何实验室异常，包括但不限于：血清总胆红素≥ 1.5 mg/dL；血清ALT或AST > 2.5 × ULN；血清肌酐≥ 2.0 mg/dL；
4. 根据纽约心脏协会功能分级，NYHA III级或IV级心力衰竭，或超声心动图显示左心室射血分数（LVEF）< 50%；
5. 肺功能异常，室内空气中氧饱和度（SpO₂）< 92%；
6. 入组前12个月内有心肌梗死、冠状动脉血管成形术或支架植入术、不稳定型心绞痛或其他临床显著严重心脏疾病史；
7. 经药物治疗后血压控制不佳的3级高血压；
8. 有创伤性脑损伤、意识障碍、癫痫或严重脑缺血性或出血性疾病史；
9. 存在自身免疫性疾病、免疫缺陷或其他需要免疫抑制治疗的情况；
10. 存在未控制的的活动性感染；
11. 既往接受过任何CAR-T细胞产品或其他基因修饰T细胞治疗；
12. 入组前4周内接种过活疫苗；
13. HIV、HBV、HCV和TPPA/RPR检测结果阳性，和/或HBV携带者；
14. 有酒精滥用、违禁药物使用或精神疾病史；
15. 入组前3个月内参加过任何其他临床研究；
16. 女性受试者符合以下任何一项：
1. 妊娠或哺乳期；或
2. 计划在研究期间妊娠；或
3. 有生育能力且无法/不愿使用有效避孕措施；
17. 研究者认为存在任何其他使受试者不适合参加本研究的情况。
Inclusion Criteria:
1. Aged 18-75 years (≥18 and ≤75 years), either sex;
2. The subject voluntarily participates in the study and provides written informed consent signed by the subject or his/her legally authorized representative;
3. Histopathologically confirmed unresectable, locally advanced, recurrent, or metastatic solid malignant tumor; according to the AJCC TNM staging system (8th edition, 2017), subjects diagnosed with stage III or stage IV solid malignant tumors;
4. Presence of measurable and evaluable lesions according to RECIST v1.1;
5. Positive MSLN expression in tumor tissue confirmed by immunohistochemistry (IHC);
6. The subject must have received standard first-line therapy and has experienced disease progression or is intolerant to such therapy;
7. The subject is not suitable for curative treatment modalities such as definitive chemoradiotherapy and/or surgery/immune checkpoint inhibitors, or refuses surgical resection;
8. No antibody-based therapy administered within 2 weeks prior to cell therapy;
9. ECOG performance status 0-2;
10. No contraindications to peripheral blood leukapheresis;
11. Estimated life expectancy ≥ 3 months.
Exclusion Criteria:
1. History of allergy to any component of the cell product;
2. Any of the following hematologic abnormalities on complete blood count (CBC): WBC ≤ 1 × 10\^9/L, absolute neutrophil count (ANC) ≤ 0.5 × 10\^9/L, absolute lymphocyte count (ALC) ≤ 0.5 × 10\^9/L, or platelets (PLT) ≤ 25 × 10\^9/L;
3. Any of the following laboratory abnormalities, including but not limited to: serum total bilirubin ≥ 1.5 mg/dL; serum ALT or AST \> 2.5 × ULN; serum creatinine ≥ 2.0 mg/dL;
4. NYHA class III or IV heart failure per the New York Heart Association functional classification, or left ventricular ejection fraction (LVEF) \< 50% on echocardiography;
5. Abnormal pulmonary function with oxygen saturation (SpO₂) \< 92% on room air;
6. History of myocardial infarction, coronary angioplasty or stenting, unstable angina, or other clinically significant severe cardiac disease within 12 months prior to enrollment;
7. Grade 3 hypertension with poor blood pressure control despite medical treatment;
8. History of traumatic brain injury, disturbance of consciousness, epilepsy, or severe cerebral ischemic or hemorrhagic disease;
9. Presence of autoimmune disease, immunodeficiency, or other conditions requiring immunosuppressive therapy;
10. Presence of uncontrolled active infection;
11. Prior treatment with any CAR-T cell product or other genetically modified T-cell therapy;
12. Receipt of a live vaccine within 4 weeks prior to enrollment;
13. Positive test results for HIV, HBV, HCV, and TPPA/RPR, and/or HBV carriers;
14. History of alcohol abuse, illicit drug use, or psychiatric disorders;
15. Participation in any other clinical study within 3 months prior to enrollment;
16. Female subjects meeting any of the following:
1. pregnant or breastfeeding; or
2. planning pregnancy during the study period; or
3. of childbearing potential and unable/unwilling to use effective contraception;
17. Any other condition that, in the opinion of the investigator, makes the subject unsuitable for participation in this study.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：TRAEs · Adverse events during treatment · From date of initial treatment to the 30 days after treatment
次要终点：Disease-related clinical responses
受试者将在计划MSLN CAR-T细胞输注前第-5、-4和-3天接受淋巴细胞清除性化疗（FC方案：Fludarabine + Cyclophosphamide）。CAR-T细胞输注将在FC化疗完成后72小时进行。
1. 研究标题： MSLN CAR-T在晚期恶性肿瘤中的疗效和安全性 2. 研究目的： 主要：评估MSLN靶向CAR-T细胞疗法在III/IV期晚期恶性肿瘤患者中的安全性和耐受性。 次要：初步评估MSLN靶向CAR-T细胞疗法在该患者群体中的疗效。 探索性：评估输注的MSLN靶向CAR-T细胞在体内的扩增和持久性，并探索与临床结局的相关性。 3. 受试者干预： 受试者将在计划MSLN CAR-T细胞输注前第-5、-4和-3天接受淋巴细胞清除性化疗（FC方案：Fludarabine + Cyclophosphamide）。CAR-T细胞输注将在FC化疗完成后72小时进行。
1. Study Title: Efficacy and safety of MSLN CAR-T in advanced malignant tumors 2. Study Objectives: Primary: To evaluate the safety and tolerability of MSLN-targeted CAR-T cell therapy in patients with stage III/IV advanced malignant tumors. Secondary: To preliminarily evaluate the efficacy of MSLN-targeted CAR-T cell therapy in this patient population. Exploratory: To assess in vivo expansion and persistence of infused MSLN-targeted CAR-T cells and explore correlations with clinical outcomes. 3. Participant Intervention: Participants will receive lymphodepleting chemotherapy (FC regimen: Fludarabine + Cyclophosphamide) on Days -5, -4, and -3 relative to the planned MSLN CAR-T cell infusion. The CAR-T cell infusion will be administered 72 hours after the completion of the FC chemotherapy.
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