肿瘤细胞治疗研究
英文原题：CAR-T Cell Therapy for ALL
这是一项早期 I 期注册临床试验，评估 CAR-T 细胞治疗急性淋巴细胞白血病的安全性、可行性及初步疗效。当前状态：招募中。计划入组 10 例。试验地点：其他 · 拉瓦尔品第（共 1 个中心）。登记号：NCT07695012。
不限性别 · ≥ 5 Years 且 ≤ 50 Years
纳入标准： 须满足以下全部条件： • 知情同意时年龄5–50岁。 • 形态学或免疫表型确认CD19阳性B细胞ALL，且符合以下至少一项复发/难治标准：第二次或以后骨髓复发；既往异基因造血干细胞移植后任何骨髓复发，且移植至计划CAR-T输注至少间隔6个月；原发难治（标准诱导化疗≥2个疗程后未达CR）或化疗难治（复发ALL标准挽救化疗≥1个疗程后未达CR）；费城染色体阳性（Ph+）ALL，对≥2线酪氨酸激酶抑制剂（TKI）不耐受/治疗失败或有TKI禁忌；因合并症、无合适供者、预处理禁忌或与非研究团队的移植医师充分讨论后拒绝移植，而不适合异基因移植。 • 入组前3个月内多参数流式细胞术确认肿瘤细胞CD19表达，CD19阳性原始细胞≥20%。 • 筛选时骨髓形态学原始细胞≥5%。 • 筛选时器官功能充分：肾功能为年龄校正血清肌酐在CTCAE儿科参考范围内，或GFR≥30 mL/min/1.73m²（MDRD/CKD-EPI）；ALT/AST≤5×ULN，总胆红素<2.0 mg/dL；筛选前28天内超声心动图LVEF≥45%或左室短轴缩短率（LVSF）≥28%；呼吸困难≤1级，室内空气SpO₂≥91%。 • 年龄≥16岁者ECOG≤2；<16岁者Lansky体能评分≥50。 • 研究者判断预期生存期>12周。 • 能耐受白细胞单采：单采时ALC≥100/μL且CD3+计数≥100/μL，或有可接受的既往储存细胞产品。 • 既往接受异基因移植者不得有活动性≥2级急性GVHD或广泛慢性GVHD；CAR-T输注前4周内未因GVHD接受全身免疫抑制治疗。 • 受试者书面知情同意；未满18岁者由父母/监护人同意，7–17岁受试者另须提供赞同。愿意且能够遵守研究程序、访视计划及长期随访，包括15年基因治疗安全监测。 • 有生育能力女性（已初潮且未经手术绝育）须在CAR-T输注前48小时内血清或尿β-hCG妊娠试验阴性。 排除标准： • 无骨髓受累的孤立髓外复发（仅中枢神经系统或睾丸）。 • 筛选时ALL活动性中枢神经系统受累，按NCCN标准为CNS-3（脑脊液细胞离心涂片有原始细胞、脑神经麻痹或脑实质病变）；既往CNS疾病经有效治疗并清除者可入组。 • Burkitt淋巴瘤/白血病（成熟B-ALL、表面免疫球蛋白阳性、FAB L3形态和/或MYC易位）；T-ALL或谱系不明白血病。 • 已知先天性骨髓衰竭综合征：范可尼贫血、Shwachman-Diamond综合征、Kostmann综合征、Diamond-Blackfan贫血或其他遗传性再障；唐氏综合征不排除。 • 既往接受任何CAR-T或过继T细胞产品。 • 筛选前4周内接受任何抗CD19治疗（包括blinatumomab），或抗CD19治疗后确认CD19抗原丢失、出现CD19阴性复发。若blinatumomab距筛选≥4周且重新筛查确认CD19阳性，则不排除。 • 既往接受非CAR病毒载体基因治疗，或接受过基因编辑细胞产品。 • 筛选时未控制的活动性细菌、真菌、病毒或寄生虫感染；经控制或治疗后可由研究者酌情允许。 • 活动性乙肝（HBsAg阳性，或HBcAb阳性且可检出HBV DNA）、活动性丙肝（抗HCV阳性且可检出HCV RNA），或筛选前8周内确认HIV阳性。 • 活动性2–4级急性GVHD，或活动性中/重度慢性GVHD。 • 过去3年内除B-ALL外的恶性肿瘤；经根治性治疗且无活动性疾病证据的宫颈或皮肤原位癌除外。 • 筛选前30天内或5个半衰期内（取较长者）接触研究药物。 • 妊娠或哺乳。 • 未控制的精神疾病或严重认知障碍，导致无法知情同意或遵守方案程序。 • 研究者认为会使研究程序给患者带来不可接受风险的任何疾病。 • CAR-T输注时使用禁用合并药物：输注前72小时内使用超过生理替代剂量的全身糖皮质激素（>12 mg/m²/日氢化可的松等效剂量）；输注前8周内接受抗T细胞抗体（ATG、阿仑单抗）；输注前4周内接受全身GVHD免疫抑制治疗；输注前6周内接受供者淋巴细胞输注。
Inclusion Criteria: * Inclusion Criteria All of the following criteria must be met for enrolment: * 1\. Age ≥5 years and ≤50 years at the time of consent * 2\. Morphologically or immunophenotypically confirmed B-cell ALL (CD19+) meeting one or more of the following relapsed/refractory criteria: * a. Second or subsequent bone marrow relapse (BM ≥2nd relapse) * b. Any BM relapse following prior allogeneic HSCT, provided ≥6 months have elapsed from SCT to planned CAR-T infusion * c. Primary refractory disease: failure to achieve CR after ≥2 cycles of standard induction chemotherapy; or chemorefractory: failure to achieve CR after ≥1 cycle of standard salvage chemotherapy for relapsed ALL * d. Philadelphia chromosome-positive (Ph+) ALL: intolerant to or failed ≥2 lines of TKI therapy, or TKI contraindicated * e. Ineligibility for allo-HSCT due to: comorbid disease, lack of suitable donor, contraindication to conditioning, or patient refusal after documented discussion with a BMT physician not part of the study team * 3\. CD19 expression on tumour cells confirmed by multi-parameter flow cytometry within 3 months of enrolment (≥20% CD19-positive blasts required) * 4\. Bone marrow blast burden ≥5% by morphological assessment at screening * 5\. Adequate organ function at screening: * a. Renal: Age-adjusted serum creatinine within normal limits per CTCAE paediatric reference tables, or GFR ≥30 mL/min/1.73m² (MDRD/CKD-EPI) * b. Hepatic: ALT/AST ≤5× ULN; Total bilirubin \<2.0 mg/dL * c. Cardiac: LVEF ≥45% or LVSF ≥28% on echocardiogram (performed within 28 days of screening) * d. Pulmonary: ≤Grade 1 dyspnoea; SpO₂ ≥91% on room air * 6\. ECOG performance status ≤2 (age ≥16 years); Lansky performance scale ≥50 (age \<16 years) * 7\. Life expectancy \>12 weeks in the opinion of the investigator * 8\. Adequate haematological status to tolerate leukapheresis (ALC ≥100/µL and CD3+ count ≥100/µL at time of apheresis, or acceptable stored product available) * 9\. Patients who have undergone prior allo-HSCT must have: (a) no active acute GVHD (Grade ≥2) or extensive chronic GVHD; (b) no systemic immunosuppression for GVHD within 4 weeks prior to CAR-T infusion * 10\. Written informed consent from patient (and parent/guardian if age \<18 years); assent from patients aged 7-17 years * 11\. Willingness and ability to comply with study procedures, visit schedule, and long-term follow-up requirements including the 15-year gene therapy safety surveillance * 12\. Negative pregnancy test (serum or urine β-hCG) within 48 hours of CAR-T infusion for females of childbearing potential (defined as post-menarche and not surgically sterilised) 4.3 Exclusion Criteria Patients meeting ANY of the following criteria will be excluded: * 1\. Isolated extra-medullary (CNS-only or testicular-only) disease relapse without bone marrow involvement * 2\. Active CNS involvement by ALL, defined as CNS-3 status per NCCN criteria (CSF blasts on cytospin, cranial nerve palsy, or brain parenchymal disease) at time of screening. Patients with prior CNS disease that has been effectively treated and cleared are eligible * 3\. Burkitt's lymphoma/leukemia (mature B-ALL with sIg positive, FAB L3 morphology and/or MYC translocation) * 4\. T-cell ALL or ambiguous lineage leukemia * 5\. Known congenital bone marrow failure syndromes: Fanconi anaemia, Shwachman-Diamond syndrome, Kostmann syndrome, Diamond-Blackfan anaemia, or any other inherited aplastic anaemia. (Down syndrome patients are NOT excluded) * 6\. Prior treatment with any CAR-T or adoptive T-cell product * 7\. Prior anti-CD19 therapy of any kind (including blinatumomab) within 4 weeks of screening; or confirmed CD19-negative (antigen-loss) relapse on anti-CD19-based therapy. \[Note: prior blinatumomab ≥4 weeks before screening is not exclusionary if CD19 positivity is confirmed at re-screening\] * 8\. Prior gene therapy with a viral vector (non-CAR gene therapy); or prior receipt of a gene-edited cellular product * 9\. Active uncontrolled infection at screening (bacterial, fungal, viral or parasitic). Patients with controlled or treated infection may be enrolled at investigator discretion * 10\. Active Hepatitis B (HBsAg positive, or anti-HBc positive with detectable HBV DNA); active Hepatitis C (anti-HCV positive with detectable HCV RNA); or HIV positive (confirmed within 8 weeks of screening) * 11\. Active Grade 2-4 acute GVHD or active moderate/severe chronic GVHD * 12\. Prior malignancy other than B-ALL in the last 3 years (except carcinoma in situ of cervix or skin treated with curative intent, with no evidence of active disease) * 13\. Investigational medicinal product (IMP) exposure within 30 days prior to screening, or within 5 half-lives, whichever is longer * 14\. Pregnant or breastfeeding women * 15\. Uncontrolled psychiatric condition or severe cognitive impairment that would preclude informed consent or compliance with protocol procedures * 16\. Any medical condition that, in the opinion of the investigator, would place the patient at unacceptable risk from the study procedures * 17\. Prohibited concomitant medications at time of CAR-T infusion (detailed in Section 6.5): * Systemic corticosteroids \>physiologic replacement (\>12 mg/m²/day hydrocortisone equivalent) within 72 hours prior to CAR-T infusion * Anti-T-cell antibody therapy (ATG, alemtuzumab) within 8 weeks prior to CAR-T infusion * Systemic GVHD immunosuppression within 4 weeks prior to CAR-T infusion * Donor lymphocyte infusion within 6 weeks prior to CAR-T infusion Exclusion Criteria: \-
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：To evaluate the safety and feasibility of autologous anti-CD19 CAR-T cell therapy manufactured at AFBMTC using the BIOCCUS lentiviral vector and CELLBRI automated expansion system in patients aged 5-50 years with relapsed or refractory B-cell ALL. · Primary Safety Incidence/grade of CRS (ASTCT) Day 0-28 · 1 year after infusion of CAR-T
在AFBMTC采用标准大容量单采技术采集未动员外周血单个核细胞，目标为儿童每公斤≥1×10⁸个CD3+ T细胞，成人至少5×10⁸个CD3+ T细胞；单采前ALC和CD3+计数均须>100/μL。采集物立即送制备或在AFBMTC经验证的条件下冻存。使用BIOCCUS提供的复制缺陷型、自失活（SIN）第三代慢病毒载体转导抗CD19 CAR基因，CAR包含抗CD19单链可变区（鼠源或人源化）、CD8α铰链/跨膜结构域、4-1BB共刺激结构域及CD3ζ活化结构域；载体3'LTR删除病毒增强子以提高安全性。
急性淋巴细胞白血病（ALL）是儿童最常见的恶性肿瘤之一，也是成人第二常见的急性白血病；约85%的ALL为B细胞型。在巴基斯坦，ALL是大型转诊中心最常见的血液系统恶性肿瘤。儿童一线联合化疗完全缓解率超过95%，但15%–20%会复发；复发后挽救化疗的二次完全缓解率为30%–50%，单靠传统化疗的长期无事件生存率低于10%。成人预后更差，即使首次完全缓解且未接受异基因移植，5年总生存率仍低于40%。原发难治或多次复发患者亟需新疗法；传统化疗后异基因造血干细胞移植受供者可及性、预处理相关死亡及移植前难以缓解等限制。
Acute lymphoblastic leukemia (ALL) is the most common malignancy in children and the second most frequent acute leukemia in adults. B-cell ALL constitutes approximately 85% of all ALL diagnoses. In Pakistan, ALL represents the most prevalent haematological malignancy presenting to tertiary centres, with AFBMTC receiving the largest national referral volume for haematological malignancies and transplantation. First-line combination chemotherapy achieves complete remission (CR) in \>95% of paediatric patients; however, 15-20% relapse. Outcomes following first relapse are substantially inferior: second-line salvage chemotherapy achieves CR2 in 30-50% of patients, and long-term event-free survival (EFS) after conventional chemotherapy alone is \<10%. Outcomes in adult ALL are even more dismal, with OS at 5 years below 40% even in first CR without allogeneic transplant. Patients with primary refractory ALL or multiply relapsed ALL have an unmet medical need for novel therapeutic approaches. The classical paradigm of chemotherapy followed by allogeneic haematopoietic stem cell transplantation (allo-HSCT) is limited by donor availability, conditioning-related mortality, and inability to achieve remission before transplant.
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