肿瘤细胞治疗研究
英文原题：U69-CART-Cells For R/R T-ALL
这是一项 I 期注册临床试验，评估 CAR-T 细胞治疗淋巴瘤的安全性、可行性及初步疗效。当前状态：招募中。计划入组 12 例。试验地点：中国 · 苏州（共 1 个中心，其中中国 1 个）。登记号：NCT07350863。
不限性别 · ≥ 15 Years 且 ≤ 75 Years
纳入标准：
* 受试者必须满足以下所有标准方可入组本研究：
1. 知情同意：自愿提供书面知情同意，且预期能够完成所有必需的研究程序和随访评估。
2. 年龄：签署知情同意书时年龄≥15岁且≤75岁。对于未成年人（年龄≤18岁），知情同意须由法定监护人提供；有签署能力的未成年人应与监护人共同签署知情同意书。
3. 诊断与疾病状态：根据2022年WHO血液淋巴肿瘤分类，经组织学或细胞学确诊为复发或难治性T细胞急性淋巴细胞白血病/淋巴瘤（T-ALL/LBL），且标准治愈性治疗不再有效。
3.1 对于T-ALL：筛选时骨髓或外周血中原始细胞≥5%。复发：定义为既往达到完全缓解（CR/CRi）后，外周血或骨髓中原始细胞再次出现（≥5%）或出现髓外病变。包括早期复发（首次缓解后12个月内）、晚期复发（≥12个月）经一个多药再诱导化疗周期后未能达到缓解，或自体或异基因造血干细胞移植（HSCT）后复发。
难治：定义为至少两个周期诱导化疗后未能达到CR，或复发后一个周期挽救治疗未能达到CR。
3.2 对于T-LBL：筛选时至少存在一个可测量病灶，定义为根据2014年Lugano标准经CT或MRI评估，淋巴结病灶长径>15 mm或结外病灶长径>10 mm。
复发/难治：定义为既往至少两线治疗后复发或疾病进展；原发难治性疾病（一线治疗后未能达到至少部分缓解，PR）；或自体或异基因HSCT后复发/进展（须经组织活检确认）。
4. 生物标志物：筛选时经骨髓样本流式细胞术和/或髓外病灶活检免疫组化确认肿瘤细胞CCR9阳性。
5. 体能状态：美国东部肿瘤协作组（ECOG）体能状态评分为0至2。
6. 预期生存期：预计生存期大于3个月。
7. 骨髓储备：筛选时骨髓储备充足，定义为：
中性粒细胞绝对计数（ANC）≥ 1.0 × 10⁹/L 淋巴细胞绝对计数（ALC）≥ 0.3 × 10⁹/L 血小板计数（PLT）≥ 20 × 10⁹/L（允许输血支持）。
8. 器官功能：器官功能充足，定义为：
肝脏：天冬氨酸氨基转移酶（AST）和丙氨酸氨基转移酶（ALT）≤ 3 × 正常上限（ULN）；总胆红素≤ 2 × ULN。
肾脏：血清肌酐 ≤ 1.5 × ULN，或肌酐清除率 ≥ 50 mL/min（按Cockcroft-Gault公式计算）。
心脏：左心室射血分数（LVEF）≥ 45%。肺：室内空气下血氧饱和度 ≥ 92%。
9. 避孕：有生育能力的女性受试者在筛选时血清妊娠试验必须为阴性，并同意在输注后至少一年内使用高效避孕措施。有生育能力女性伴侣的男性受试者必须同意使用屏障避孕措施，并在输注后至少一年内禁止捐献精子。
10. 白细胞分离术：必须具有足够的静脉通路以进行白细胞分离术或静脉采血，且无其他白细胞分离术禁忌症。
排除标准：
* 如果受试者符合以下任何一项标准，将被排除在研究之外：
1. 筛选前3年内诊断出任何其他恶性肿瘤，但已完成治愈性治疗且达到3年以上无病生存、研究者判断复发风险较低者除外（例如，肺原位癌、皮肤基底细胞癌）。
2. 筛选时或既往存在与研究疾病无关的中枢神经系统（CNS）疾病史或现症，如癫痫、脑缺血/出血、痴呆、小脑疾病或任何累及CNS的自身免疫性疾病。
3. 既往接受过靶向CCR9的细胞治疗，包括但不限于CAR-T或CAR-γδT细胞。
4. 存在显著或活动性CNS实质或颅神经病变，研究者判断风险大于获益。
5. 在单采前 ≤72 小时内停用全身性皮质类固醇，但生理替代剂量除外（例如，泼尼松 <10 mg/天或等效剂量）。
6. 单采前6周内接受过供者淋巴细胞输注（DLI）。
7. 单采前4周内接受过任何抗T细胞抗体治疗。
8. 存在以下任何一项：乙型肝炎e抗体（HBe-Ab）和/或乙型肝炎核心抗体（HBc-Ab）阳性且HBV-DNA高于定量下限；丙型肝炎抗体（HCV-Ab）阳性且HCV-RNA高于定量下限；梅毒螺旋体抗体（TP-Ab）阳性；人类免疫缺陷病毒（HIV）抗体检测阳性；或定量PCR检测EBV-DNA或CMV-DNA水平高于定量下限。
9. 筛选时存在需要全身治疗的活動性或未控制的感染（不包括轻度泌尿生殖道或上呼吸道感染），由研究者评估。
10. 知情同意前12个月内接受过冠状动脉血管成形术或支架置入术；纽约心脏病协会（NYHA）III-IV级充血性心力衰竭；6个月内发生心肌梗死、不稳定型心绞痛或其他研究者判定为不适合入组的具有临床意义的心脏疾病；筛选时QTc间期>480 ms（采用Fridericia公式计算）；或尽管接受标准治疗仍存在未控制的高血压（收缩压≥160 mmHg和/或舒张压≥100 mmHg）或肺动脉高压。
11. 研究者判断存在不稳定的全身性疾病，包括但不限于需要药物干预的严重肝脏、肾脏或代谢性疾病。
12. 活动性或未控制的自身免疫性疾病，或原发性/继发性免疫缺陷。
13. 对研究中所使用的任何药物有严重速发型超敏反应史。
14. 筛选前6周内接种过任何活疫苗。
15. 妊娠或哺乳期个体。
16. 过去2年内有需要全身免疫抑制或疾病修饰药物治疗的自身免疫性疾病史（如克罗恩病、类风湿关节炎、系统性红斑狼疮）。
17. 单采前12周内接受过异基因造血干细胞移植；筛选前4周内存在急性或中重度慢性GVHD；或细胞输注前4周内接受过任何全身性GVHD治疗，包括需要合并使用皮质类固醇者。
18. 筛选前4周内参加过任何其他干预性临床试验。
19. 无法遵守研究程序，或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:
* Subjects must meet all of the following criteria to be eligible for the study:
1. Informed Consent: Voluntary provision of written informed consent and anticipated ability to complete all required study procedures and follow-up assessments.
2. Age: ≥15 and ≤75 years of age at the time of signing the informed consent form.For minors (age ≤ 18 years), informed consent must be provided by a legal guardian; minors with capacity to sign should co-sign the consent form alongside their guardian.
3. Diagnosis and Disease Status: Histologically or cytologically confirmed diagnosis of relapsed or refractory T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) according to the 2022 WHO Classification of Haematolymphoid Tumours, for which standard curative treatments are no longer effective.
3.1 For T-ALL: Presence of ≥5% blasts in bone marrow or peripheral blood at screening. Relapse: Defined as recurrence of blasts (≥5%) in peripheral blood or bone marrow or emergence of extramedullary disease after prior achievement of complete remission (CR/CRi). This includes early relapse (within 12 months of first remission), late relapse (≥12 months) failing to achieve remission after one multi-agent re-induction chemotherapy cycle, or relapse after autologous or allogeneic hematopoietic stem cell transplantation (HSCT).
Refractory: Defined as failure to achieve CR after at least two cycles of induction chemotherapy, or failure to achieve CR after one cycle of salvage therapy following relapse.
3.2 For T-LBL: Presence of at least one measurable lesion at screening, defined as a nodal lesion with a long axis \>15 mm or an extranodal lesion with a long axis \>10 mm, as assessed by CT or MRI per the 2014 Lugano criteria.
Relapsed/Refractory: Defined as relapse or disease progression after at least two prior lines of therapy; primary refractory disease (failure to achieve at least a partial response, PR, after first-line therapy); or relapse/progression after autologous or allogeneic HSCT (must be confirmed by tissue biopsy).
4. Biomarker: Confirmed CCR9 positivity on tumor cells via flow cytometry of bone marrow samples and/or via immunohistochemistry of extramedullary lesion biopsies at screening.
5. Performance Status: Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
6. Life Expectancy: Estimated life expectancy of greater than 3 months.
7. Bone Marrow Reserve: Adequate bone marrow reserve at screening, defined as:
Absolute Neutrophil Count (ANC) ≥ 1.0 × 10⁹/L Absolute Lymphocyte Count (ALC) ≥ 0.3 × 10⁹/L Platelet Count (PLT) ≥ 20 × 10⁹/L (transfusion support is permitted).
8. Organ Function: Adequate organ function defined as:
Hepatic: Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 3 × Upper Limit of Normal (ULN); Total Bilirubin ≤ 2 × ULN.
Renal: Serum Creatinine ≤ 1.5 × ULN, OR Creatinine Clearance ≥ 50 mL/min (calculated by the Cockcroft-Gault formula).
Cardiac: Left Ventricular Ejection Fraction (LVEF) ≥ 45%. Pulmonary: Oxygen saturation ≥ 92% on room air.
9. Contraception: Female subjects of childbearing potential must have a negative serum pregnancy test at screening and agree to use highly effective contraception for at least one year post-infusion. Male subjects with female partners of childbearing potential must agree to use barrier contraception and refrain from sperm donation for at least one year post-infusion.
10. Leukapheresis: Must have adequate venous access for leukapheresis or venous blood draw and no other contraindications to leukapheresis.
Exclusion Criteria:
* Subjects will be excluded from the study if they meet any of the following criteria:
1. Diagnosis of any other malignancy within 3 years prior to screening, except for those who have completed curative therapy and achieved over 3 years of disease-free survival with a low risk of recurrence as determined by the investigator (e.g., carcinoma in situ of the lung, basal cell carcinoma of the skin).
2. History or presence of central nervous system (CNS) disorders unrelated to the disease under study at screening or previously, such as seizure, cerebral ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease involving the CNS.
3. Prior receipt of cell therapies targeting CCR9, including but not limited to CAR-T or CAR-γδT cells.
4. Significant or active parenchymal CNS or cranial nerve lesions where, in the investigator's judgment, the risks outweigh the benefits.
5. Systemic corticosteroid use discontinued ≤72 hours prior to apheresis, except for physiological replacement doses (e.g., prednisone \<10 mg/day or equivalent).
6. Donor lymphocyte infusion (DLI) within 6 weeks prior to apheresis.
7. Treatment with any anti-T-cell antibody therapy within 4 weeks prior to apheresis.
8. Presence of any of the following: positive hepatitis B e antibody (HBe-Ab) and/or hepatitis B core antibody (HBc-Ab) with HBV-DNA above the lower limit of quantification; positive hepatitis C antibody (HCV-Ab) with HCV-RNA above the lower limit of quantification; positive treponema pallidum antibody (TP-Ab); positive human immunodeficiency virus (HIV) antibody test; or EBV-DNA or CMV-DNA levels above the lower limit of quantification by quantitative PCR.
9. Active or uncontrolled infection requiring systemic therapy at the time of screening (excluding mild genitourinary or upper respiratory tract infections), as assessed by the investigator.
10. Coronary angioplasty or stent placement within 12 months prior to informed consent; congestive heart failure of New York Heart Association (NYHA) Class III-IV; myocardial infarction, unstable angina, or other clinically significant cardiac conditions within 6 months deemed ineligible by the investigator; QTc interval \>480 ms (calculated using Fridericia's formula) at screening; or uncontrolled hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg) or pulmonary hypertension despite standard treatment.
11. Unstable systemic diseases per investigator judgment, including but not limited to severe hepatic, renal, or metabolic diseases requiring pharmacological intervention.
12. Active or uncontrolled autoimmune disease, or primary/secondary immunodeficiency.
13. History of severe immediate hypersensitivity to any drug used in the study.
14. Administration of any live vaccine within 6 weeks prior to screening.
15. Pregnant or lactating individuals.
16. History of autoimmune disease requiring systemic immunosuppressive or disease-modifying medication within the past 2 years (e.g., Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus).
17. Allogeneic hematopoietic stem cell transplantation within 12 weeks prior to apheresis; presence of acute or moderate-to-severe chronic GVHD within 4 weeks prior to screening; or any systemic GVHD treatment within 4 weeks prior to cell infusion, including those requiring concomitant corticosteroid use.
18. Participation in any other interventional clinical trial within 4 weeks prior to screening.
19. Inability to comply with study procedures, or any other condition considered by the investigator to render the subject unsuitable for the 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) · 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 CXCR4 CCR9 CAR-T cell infusion；Adverse Event (AE） · 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；The Recommended Phase II Dose（RP2D） · The dose recommended for use in phase 2 studies on the basis of dose limiting toxicities observed in phase 1 studies. · Within 28 days after CXCR4 CCR9 CAR-T cell infusion
次要终点：Objective Response Rate (ORR)；MRD-negative rate (for T-ALL)；Duration of Response (DOR)；Progression-Free Survival (PFS)；Event-Free Survival (EFS)；Overall Survival (OS)；Pharmacokinetics-AUC(0-28)；Pharmacokinetics-Cmax
研究产品为CXCR4增强的CCR9嵌合抗原受体T细胞注射液（CXCR4/CCR9 CAR-T，U69）。各队列的计划剂量为： 低剂量队列：每公斤体重1 × 10⁶个CAR阳性T细胞。产品以单次静脉输注方式给药。实际给药剂量在目标剂量的70%至130%范围内可接受。所需细胞数将根据受试者单采时的体重计算。研究者可根据受试者的具体临床情况调整最终细胞剂量。
研究产品为CXCR4增强的CCR9嵌合抗原受体T细胞注射液（CXCR4/CCR9 CAR-T，U69）。各队列的计划剂量为： 中剂量队列：每公斤体重3 × 10⁶个CAR阳性T细胞。产品以单次静脉输注方式给药。实际给药剂量在目标剂量的70%至130%范围内可接受。所需细胞数将根据受试者单采时的体重计算。研究者可根据受试者的具体临床情况调整最终细胞剂量。
研究产品为CXCR4增强的CCR9嵌合抗原受体T细胞注射液（CXCR4/CCR9 CAR-T，U69）。各队列的计划剂量为： 高剂量队列：每公斤体重6 × 10⁶个CAR阳性T细胞。产品以单次静脉输注方式给药。实际给药剂量在目标剂量的70%至130%范围内可接受。所需细胞数将根据受试者单采时的体重计算。研究者可根据受试者的具体临床情况调整最终细胞剂量。
总体介绍 这项单臂、开放标签临床试验旨在评估CXCR4 enabled CCR9嵌合抗原受体T细胞注射液（CXCR4 CCR9 CAR-T）在复发或难治性T淋巴母细胞白血病/淋巴瘤（r/r T-ALL/LBL）患者中的安全性、耐受性、药代动力学和药效学。此外，本研究旨在初步评估CXCR4 CCR9 CAR-T细胞的疗效，并探索后续II期临床试验的合适剂量和给药方案。采用3+3设计的剂量递增研究在三个剂量队列中实施，每个队列计划入组3至6名患者，总计9至18名受试者。细胞输注后，受试者接受安全性和疗效随访，随访持续至输注后2年、受试者退出或研究终止——以先发生者为准。对于研究完成或提前终止后有可用随访信息的受试者，进行长期随访——包括长期安全性监测——最长可达15年。
Overall Introduction This single-arm, open-label clinical trial aims to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of CXCR4-enabled CCR9 chimeric antigen receptor T-cell injection (CXCR4 CCR9 CAR-T) in patients with relapsed or refractory T-lymphoblastic leukemia/lymphoma (r/r T-ALL/LBL). Additionally, the study seeks to preliminarily assess the efficacy of CXCR4 CCR9 CAR-T cells and explore the appropriate dosage and administration schedule for subsequent Phase II clinical trials. A dose escalation study following the 3+3 design was implemented across three dose cohorts, with each cohort planned to enroll 3 to 6 patients, totaling 9 to 18 participants. Following cell infusion, subjects underwent safety and efficacy follow-up, which continued until 2 years post-infusion, subject withdrawal, or study termination-whichever occurred first. For subjects with available follow-up information after study completion or early termination, long-term follow-up-including long-term safety monitoring-was conducted for up to 15 years.
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