肿瘤细胞治疗研究
英文原题：U96-CAR-T-Cells For R/R B-ALL
这是一项 I 期注册临床试验，评估细胞治疗用于淋巴瘤的安全性、可行性及初步疗效。当前状态：尚未开始招募。计划入组 30 例。试验地点：中国 · 苏州（共 1 个中心，其中中国 1 个）。登记号：NCT07511426。
不限性别 · ≥ 18 Years
纳入标准：
* （以下所有项目必须同时满足）
1. 患者必须自愿签署知情同意书，且依从性良好；
2. 针对不同适应症，患者必须满足以下要求：
2-1）急性B淋巴细胞白血病组患者：
1. 签署知情同意书时年龄≥18岁，男女均可；
2. 根据美国国家综合癌症网络（NCCN）急性淋巴细胞白血病临床实践指南（2024年第2版）标准，明确诊断为急性B淋巴细胞白血病；
3. 根据《中国成人急性淋巴细胞白血病诊断与治疗指南》（2021年版），必须满足以下条件之一：a. 难治性白血病：标准诱导治疗（一般指4周方案或Hyper-CVAD方案）完成后未达到CR/CRi；b. 白血病复发：已获得CR的患者外周血或骨髓中原始细胞（比例>5%）或MRD阳性或髓外病变；2-2）B细胞淋巴瘤组患者：
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1. 签署知情同意书时年龄≥18岁，男女均可；
2. 根据美国国家综合癌症网络（NCCN）B细胞淋巴瘤临床实践指南（2024年第3版）标准，明确诊断为B细胞淋巴瘤；
3. 至少二线治疗（一种标准化疗方案+一种挽救化疗）失败或筛选前复发的B细胞淋巴瘤患者。B细胞淋巴瘤既往治疗必须包括CD20单克隆抗体（排除CD20阴性肿瘤患者）和以蒽环类药物为基础的标准化疗方案。必须满足以下条件之一：a. 无法接受自体造血干细胞移植；b. 拒绝接受自体造血干细胞移植；c. 自体造血干细胞移植后复发；
4. 筛选时，患者处于疾病复发或难治状态：a）复发定义：经过充分治疗达到缓解（包括部分缓解（PR）或完全缓解（CR））后，再次出现PD；b）难治定义：i. 对末次治疗无反应：末次治疗期间/之后出现PD或最佳疗效为SD，且持续时间小于6个月；ii. ASCT后复发或进展（需活检确认），包括：ASCT后12个月内复发或PD，若接受挽救治疗，对末次治疗无反应（SD或PD）；
3. 骨髓或外周血或免疫组化或病理学显示CD19抗原阳性；
4. 根据Lugano淋巴瘤疗效评价标准（Cheson 2014），B细胞淋巴瘤患者至少有一个可评估病灶，或经PET-CT确认的阳性病灶；
5. 美国东部肿瘤协作组（ECOG）体能状态评分为0-3分；
6. 筛选时具有一定程度的骨髓储备，定义为：绝对淋巴细胞值（ALC）≥ 0.3×109/L，血小板（PLT）≥ 30×109/L（允许给药后结果）；
7. 具有适当的器官功能，且需符合以下标准：天冬氨酸氨基转移酶（AST）≤ 3倍正常值上限（ULN）；丙氨酸氨基转移酶（ALT）≤ 3倍ULN（因肿瘤浸润导致的肝功能异常，需AST和ALT ≤ 5倍ULN）；血清总胆红素应≤ 2倍ULN，但Gilbert综合征合并症者除外；总胆红素应≤ 3倍ULN且直接胆红素应≤ 1.5倍ULN。符合这些标准的Gilbert综合征患者可以入组。血清肌酐应≤ 1.5倍ULN，或肌酐清除率应≥ 60 mL/min（Cockcroft and Gault公式）；具有最低水平的肺储备，定义为呼吸困难≤ 1级且非吸氧状态下血氧饱和度> 91%；超声心动图左心室射血分数应≥ 50%；国际标准化比值（INR）应≤ 1.5倍ULN，活化部分凝血活酶时间（APTT）应≤ 1.5倍ULN；
8. 育龄期女性在筛选期血/尿妊娠试验应为阴性。任何有生育能力的男性和女性患者必须同意在整个研究过程中以及研究治疗给药后至少1年内使用有效的避孕方法；
9. 预期生存期应大于3个月。
排除标准：
* （符合以下任何一条者将不能参加）
1. 患有其他恶性肿瘤且研究者认为其他恶性肿瘤的存在可能影响当前治疗；
2. 符合以下任何一条：乙型肝炎表面抗原（HBsAg）或乙型肝炎核心抗体（HBc-Ab）阳性，且HBV-DNA拷贝数大于最低检测限；丙型肝炎抗体（HCV-Ab）阳性，且HCV-RNA拷贝数大于最低检测限；抗支原体抗体（TP-Ab）阳性；人类免疫缺陷病毒（HIV）抗体阳性；
3. 存在细菌、真菌、病毒、支原体或其他类型的感染且研究者判断难以控制；
4. 既往或目前患有本病以外的中枢神经系统疾病，如癫痫发作、脑缺血/出血、痴呆、小脑疾病或任何中枢神经系统相关的自身免疫性疾病，且研究者判断为不可控制；
5. 在签署知情同意书前，12个月内接受过心脏血管成形术或支架置入术，或患有NYHA分级III-IV级充血性心力衰竭，或患有心肌梗死、不稳定型心绞痛，或研究者判断存在有临床意义的心脏病史，或患者QTc间期> 480 ms（QTc间期采用Fridericia公式计算），且心脏超声左心室射血分数< 50%；
6. 原发性免疫缺陷患者；
7. 对本研究中使用的任何药物有严重的速发型超敏反应；
8. 筛选前6周内接种过活疫苗；
9. 妊娠或哺乳期妇女；
10. 活动性自身免疫性疾病；
11. 在签署知情同意书时患有活动性急性或慢性移植物抗宿主病（GVHD），且研究者判断为不可控制；
12. 在签署知情同意书前30天内参加过任何其他干预性临床研究；
13. 研究者认为不适合参加本研究的情况。
Inclusion Criteria:
* (All the following items must be met simultaneously)
1. Patients must voluntarily sign the informed consent form and have good compliance;
2. For different indications, patients must meet the following requirements:
2-1) Patients in the acute B lymphoblastic leukemia group:
1. The age at signing the informed consent form is ≥ 18 years old, both male and female are acceptable;
2. According to the standards of the National Comprehensive Cancer Network (NCCN) Acute Lymphoblastic Leukemia Clinical Practice Guidelines (2024, 2nd Edition), it is clearly diagnosed as acute B lymphoblastic leukemia;
3. According to the "Chinese Adult Acute Lymphoblastic Leukemia Diagnosis and Treatment Guidelines" (2021 Edition), one of the following conditions must be met: a. Refractory leukemia: standard induction therapy fails to achieve CR/CRi after (generally referring to 4-week regimen or Hyper-CVAD regimen) completion; b. Leukemia recurrence: patients who have achieved CR have peripheral blood or bone marrow with blast cells (proportion \> 5%) or MRD positive or extramedullary lesions; 2-2) Patients in the B-cell lymphoma group:
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1. The age at signing the informed consent form is ≥ 18 years old, both male and female are acceptable;
2. According to the standards of the National Comprehensive Cancer Network (NCCN) B-cell lymphoma clinical practice guidelines (2024, 3rd Edition), it is clearly diagnosed as B-cell lymphoma;
3. Patients with B-cell lymphoma who have failed at least two-line treatment (one standardized chemotherapy regimen + one salvage chemotherapy) or have relapsed before screening. The previous treatment of B-cell lymphoma must include CD20 monoclonal antibody (excluding CD20-negative tumor patients) and anthracycline-based standardized treatment regimen. At least one of the following conditions must be met: a. Unable to undergo autologous hematopoietic stem cell transplantation; b. Refuse to undergo autologous hematopoietic stem cell transplantation; c. Relapse after autologous hematopoietic stem cell transplantation;
4. At screening, the patient is in a state of disease recurrence or refractory: a) Recurrence definition: after adequate treatment achieving remission (including partial remission (PR) or complete remission (CR)), PD again occurs; b) Refractoriness definition: i. No response to the last treatment: PD during/after the last treatment or the best efficacy is SD, and the duration is less than 6 months; ii. Recurrence or progression after ASCT (requiring biopsy confirmation), including: recurrence or PD within 12 months after ASCT, if salvage treatment is received, no response (SD or PD) to the last treatment;
3. Bone marrow or peripheral blood or immunohistochemistry or pathology shows CD19 antigen positive;
4. According to the Lugano Lymphoma Response Evaluation Criteria (Cheson 2014), B-cell lymphoma patients have at least one evaluable lesion, or positive lesions confirmed by PET-CT;
5. Eastern Cooperative Oncology Group (ECOG) performance status score is 0-3;
6. At screening, there is a certain degree of bone marrow reserve, defined as: absolute lymphocyte value (ALC) ≥ 0.3×109/L, platelet (PLT) ≥ 30×109/L (allowing the result after administration);
7. Have appropriate organ function, and need to meet the following standards: aspartate aminotransferase (AST) ≤ 3 times the upper limit of normal (ULN); alanine aminotransferase (ALT) ≤ 3 times ULN (for liver function abnormalities caused by tumor infiltration, AST and ALT ≤ 5 times ULN are required); total serum bilirubin The serum bilirubin should be ≤ 2 times the ULN, except for those with Gilbert syndrome who have a combined condition; the total bilirubin should be ≤ 3 times the ULN and the direct bilirubin should be ≤ 1.5 times the ULN. Patients with Gilbert syndrome who meet these criteria can be included. The serum creatinine should be ≤ 1.5 times the ULN, or the creatinine clearance rate should be ≥ 60 mL/min (Cockcroft and Gault formula); possess the lowest level of pulmonary reserve, defined as ≤ 1 grade of dyspnea and a blood oxygen saturation \> 91% in non-oxygenated state; left ventricular ejection fraction of the left heart in echocardiography should be ≥ 50%; International Normalized Ratio (INR) should be ≤ 1.5 times the ULN, and activated partial thromboplastin time (APTT) should be ≤ 1.5 times the ULN;
8. The blood/urine pregnancy test for women of childbearing age during the screening period should be negative. Any male or female patient with reproductive capacity must agree to use an effective contraceptive method throughout the study process and for at least 1 year after the administration of the study treatment;
9. The expected survival period should be greater than 3 months.
Exclusion Criteria:
* (Any of the following conditions will disqualify one from participating)
1. Having another malignant tumor and the investigator considers that the presence of other malignant tumors may affect the current treatment;
2. Any of the following conditions: positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBc-Ab), and the HBV-DNA copy number is greater than the minimum detection limit; positive for hepatitis C antibody (HCV-Ab), and the HCV-RNA copy number is greater than the minimum detection limit; positive for anti-mycoplasma antibody (TP-Ab); positive for human immunodeficiency virus (HIV) antibody;
3. Existing bacterial, fungal, viral, mycoplasma or other types of infections and the investigator determines that they are difficult to control;
4. Having a CNS disease other than this disease in the past or currently, such as epileptic seizures, cerebral ischemia/hemorrhage, dementia, cerebellar disease or any CNS-related autoimmune disease, and the investigator determines that it is uncontrollable;
5. Before signing the informed consent form, having undergone cardiac angioplasty or stent placement within 12 months, or having NYHA classification III-IV grade congestive heart failure, or having myocardial infarction, unstable angina pectoris or the investigator determines that there is a clinically significant history of heart disease, or the patient's QTc interval is \> 480 ms (QTc interval calculated using the Fridericia formula), and the left ventricular ejection fraction of the heart ultrasound is \< 50%;
6. Patients with primary immunodeficiency;
7. Having had a severe immediate-type hypersensitivity reaction to any drug used in this study;
8. Having received live vaccines within 6 weeks before screening;
9. Pregnant or lactating women;
10. Active autoimmune diseases;
11. Having active acute or chronic graft-versus-host disease (GVHD) at the time of signing the informed consent form, and the investigator determines that it is uncontrollable;
12. Participating in any other interventional clinical research within 30 days before signing the informed consent form;
13. Situations that the investigator deems unsuitable for participating 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：Dose-limiting toxicity (DLT) · Description: DLT refers to any of the following conditions occurring within 28 days after cell reinfusion that are related to cell infusion: ① Hematologic DLT: Grade 4 toxicity (excluding lymphopenia) not caused by the underlying disease and taking more than 30 days to resolve to ≤ Grade 2. ② Non-hematologic DLT: Any toxicity ≥ Grade 4 that is possibly related to CAR-T therapy, or Grade 3 toxicity that requires ≥7 days to resolve to ≤ Grade 2 or to return to baseline. · Within 28 days after U96 infusion；Adverse Event (AE） · Description: Record the types, occurrence frequency and severity of adverse events (AEs) related to CAR-T, with specific definitions determined according to CTCAE v5.0.The CRS and ICANS ratings do not use CTCAE but adopt the evaluation criteria in the ASTCT standards. · 2 years
次要终点：Objective Response Rate (ORR)；MRD-negative rate (for B-ALL)；Duration of Response (DOR)；Best Overall Response (BOR)；Overall Survival (OS)；Progression-Free Survival (PFS)；Relapse-Free Survival (RFS)；Event-Free Survival (EFS)
研究产品：U96（靶向CD7的慢病毒载体，用于体内生产IL-6敲低CD19 CAR）剂量：剂量为0.2 × 10^9 TU。给药方式：静脉注射，单次给药。
研究产品：U96（靶向CD7的慢病毒载体，用于体内生产IL-6敲低CD19 CAR）剂量：剂量为0.4× 10^9 TU。给药方式：静脉注射，单次给药。
研究产品：U96（靶向CD7的慢病毒载体，用于体内生产IL-6敲低CD19 CAR）剂量：剂量为0.8× 10^9 TU。给药方式：静脉注射，单次给药。
研究产品：U96（靶向CD7的慢病毒载体，用于体内生产IL-6敲低CD19 CAR）剂量：剂量为1.6× 10^9 TU。给药方式：静脉注射，单次给药。
研究产品：U96（靶向CD7的慢病毒载体，用于体内生产IL-6敲低CD19 CAR）剂量：剂量为0.2 × 10^9 TU。给药方式：静脉注射，单次给药。
研究产品：U96（靶向CD7的慢病毒载体，用于体内生产IL-6敲低CD19 CAR）剂量：剂量为0.4 × 10^9 TU。给药方式：静脉注射，单次给药。
研究产品：U96（靶向CD7的慢病毒载体，用于体内生产IL-6敲低CD19 CAR）剂量：剂量为0.8× 109 TU。给药方式：静脉注射，单次给药。
研究产品：U96（靶向CD7的慢病毒载体，用于体内生产IL-6敲低CD19 CAR）剂量：剂量为1.6× 109 TU。给药方式：静脉注射，单次给药。
本研究是一项单臂、开放标签的临床研究，旨在评估CAR-T（U96）治疗复发/难治性B细胞肿瘤的耐受性、安全性和初步疗效。本研究将在急性B淋巴细胞白血病和B细胞淋巴瘤两种疾病类型中开展，采用“3+3”方法进行剂量递增计划。每个剂量组计划入组3至6例患者，整个研究共约30至48例患者入组。患者在签署知情同意书后将接受筛选检查。如果符合入组和排除标准，将被纳入研究。接受U96治疗后，患者将接受随访。建议给药后住院至少14天。将在治疗后28天以及3、6、12、18和24个月进行安全性和疗效随访。治疗后随访期将持续2年，并进行15年的长期随访，以评估疗效和安全性，直至研究结束或患者退出研究。对于已接受U96治疗的患者，即使提前退出研究，研究者仍应按照方案进行长期安全性随访，以评估产品的长期安全性。
This study is a single-arm, open-label clinical investigation to evaluate the tolerance, safety and preliminary efficacy of CAR-T (U96) in the treatment of relapsed/refractory B-cell tumors. The study will be conducted in two disease types, acute B-lymphoblastic leukemia and B-cell lymphoma, with a dose escalation plan using the "3+3" method. Each dose group is planned to enroll 3 to 6 patients, with a total of approximately 30 to 48 patients to be enrolled in the entire study. After signing the informed consent form, patients will undergo screening tests. If they meet the inclusion and exclusion criteria, they will be enrolled in the study. After receiving U96 treatment, patients will be followed up. It is recommended that they stay in the hospital for at least 14 days after administration. Safety and efficacy follow-ups will be conducted at 28 days and 3, 6, 12, 18, and 24 months after treatment. The follow-up period after treatment will last for 2 years, with a long-term follow-up of 15 years to assess the efficacy and safety until the end of the study or the patient withdraws from the study. For patients who have received U96 treatment, even if they withdraw from the study early, the investigators should still conduct long-term safety follow-ups according to the protocol to evaluate the long-term safety of the product.
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