肿瘤细胞治疗研究
英文原题：Immunotherapy Using CAR T-cells to Target CD19 for Relapsed/Refractory CD19+ Primary CNS Lymphoma
Immunotherapy Using CAR T-cells to Target CD19 for Relapsed/Refractory CD19+ Primary CNS Lymphoma
这是一项 I 期注册临床试验，评估 CD19CAR-T 细胞治疗淋巴瘤的安全性、可行性及初步疗效。当前状态：进行中（不再招募）。计划入组 12 例。试验地点：欧洲 · 伦敦（共 1 个中心）。登记号：NCT04443829。
不限性别 · ≥ 16 Years
纳入标准： 1. 年龄≥16岁； 2. 组织学确诊弥漫大B细胞淋巴瘤（DLBCL），病灶局限于中枢神经系统（原发性CNS淋巴瘤，PCNSL）； 3. 复发或难治性CD19阳性PCNSL：接受一线或多线含大剂量甲氨蝶呤方案后，达到CR/CRu/PR后疾病进展，或未达到PR。条件允许时建议复发时再次活检确认；如可提供初次诊断组织且神经放射科阅片确认当前MRI表现符合PCNSL，则无再次活检也可入组； 4. 增强MRI可见可测量疾病； 5. 治疗医生判断不适合接受其他挽救治疗； 6. 同意进行妊娠检测并在适用时使用高效避孕措施； 7. 已签署书面知情同意书。部分PCNSL患者因疾病相关神经系统影响可能无法自行同意，可由法定代理人代为同意。 登记阶段排除标准： 1. CD19阴性疾病； 2. 有继发性CNS淋巴瘤证据； 3. 既往接受异基因造血干细胞移植； 4. 活动性乙型肝炎、丙型肝炎或HIV感染； 5. 室内空气下血氧饱和度≤90%； 6. 胆红素>正常值上限2倍； 7. 肾小球滤过率（GFR）<50 mL/min； 8. 妊娠期或哺乳期女性； 9. 不能耐受白细胞单采； 10. ECOG评分3–4分； 11. 已知对人血清白蛋白或二甲基亚砜（DMSO）过敏； 12. 预期生存期<3个月； 13. 心律失常或显著心脏病且左心室射血分数<40%； 14. 既往神经系统疾病（基础血液系统恶性肿瘤累及CNS除外）； 15. 存在使用PD-1抗体帕博利珠单抗的任何禁忌证； 16. 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），并造成终末器官损伤，或过去24个月内需要全身免疫抑制/疾病修饰药物治疗； 17. 筛查时胸部CT或PET-CT提示活动性肺炎，或有药物性肺炎、特发性肺纤维化、机化性肺炎（如闭塞性细支气管炎）或特发性肺炎史。放疗野内既往放射性肺炎（纤维化）者，如事件已过去>24周，可入组。 CD19 CAR-T细胞输注阶段（剂量1静脉给药及剂量2脑室内给药）排除标准： 1. 计划输注CD19 CAR-T细胞时存在严重并发感染； 2. 计划输注时需要补充氧气或存在活动性肺部浸润； 3. 仅适用于主题2：剂量1输注后出现归因于ATIMP的3或4级ICANS；主题1剂量1静脉输注后出现的1–2级神经毒性在计划主题2第二次脑室内输注前尚未完全恢复；剂量1输注后出现3–4级CRS；主题1剂量1后出现的2级CRS在计划主题2第二次输注前未恢复至≤1级；或妊娠。
Inclusion Criteria: 1. Age ≥16 2. Patients with a histologically confirmed Diffuse Large B-Cell Lymphoma (DLBCL) confined to the CNS (Primary CNS Lymphoma (PCNSL)) 3. Relapsed\* or refractory CD19+ PCNSL, defined as disease progression following CR/CRu/PR, or failure to achieve PR, after one or more lines of a high-dose methotrexate-containing protocol \*Histological confirmation by re-biopsy at relapse is recommended if feasible. However, patients will be eligible without re-biopsy provided the initial diagnostic material is available and current MRI imaging features are consistent with PCNSL by neuroradiology review. 4. Measurable disease on contrast-enhanced MRI 5. Unsuitable for alternative salvage therapies as determined by their treating physician 6. Agreement to have a pregnancy test, use highly effective contraception (if applicable) 7. Written informed consent\*\* \*\* Some patients with PCNSL may be incapable of providing their own consent due to the neurological effects of their disease. In these cases a legal representative may be sought to provide consent'. Exclusion Criteria (Registration): 1. CD19 negative disease 2. Evidence of secondary CNS lymphoma 3. Prior allogeneic haematopoietic stem cell transplant 4. Active hepatitis B, C or HIV infection 5. Oxygen saturation ≤90% on air 6. Bilirubin \>2 x upper limit of normal 7. Glomerular Filtration Rate (GFR) \<50ml/min 8. Women who are pregnant or breast feeding 9. Inability to tolerate leucapheresis 10. ECOG 3-4 11. Known allergy to albumin or Dimethyl sulfoxide (DMSO) 12. Life expectancy \<3months 13. Arrhythmias or significant cardiac disease and left ventricular ejection fraction \<40% 14. Pre-existing neurological disorders (other than CNS involvement of underlying haematological malignancy) 15. Any contraindications to PD-1 antibody Pembrolizumab 16. History of autoimmune disease (e.g. Crohn's, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 24 months 17. Evidence of active pneumonitis on chest computed tomography (CT) or positron emission tomography (PET)-CT scan at screening or history of drug-induced pneumonitis, idiopathic pulmonary fibrosis, organising pneumonia (e.g. bronchiolitis obliterans), or idiopathic pneumonitis. Prior radiation pneumonitis in the radiation field (fibrosis) is allowed (if \>24 weeks since the event) Exclusion criteria: for CD19CAR T-cell infusion ( Dose 1/i.v. and Dose 2/intraventricular): 1. Severe intercurrent infection at the time of scheduled CD19CAR T-cell infusion 2. Requirement for supplementary oxygen or active pulmonary infiltrates at the time of scheduled CD19CAR T-cell infusion 3. Theme 2 only: 1. presence of grade 3 or 4 ICANS casually related to the ATIMP following infusion of Dose 1 2. grade 1-2 neurotoxicity (if occurred) following Theme 1 dosing (Dose 1/i.v CD19CAR Tcell dose) that has not fully resolved prior to proposed administration of 2nd CD19CAR T-cell infusion (Dose /intraventricular) for theme 2 3. grade 3-4 CRS following infusion of Dose 1 4. persisting grade 2 CRS following Theme 1 dosing (Dose 1/i.v CD19CAR T-cell dose) that has not resolved to ≤ grade 1 CRS prior to proposed administration of 2nd CD19CAR Tcell infusion (Dose 2/intraventricular) for theme 2 5. pregnancy
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：Toxicity evaluated by the incidence of grade 3-5 toxicity causally related to the ATIMP · Toxicity following CD19CAR T-cell administration as evaluated by the incidence of grade 3-5 toxicity causally related to the ATIMP · 28 days；Feasibility of manufacturing CD19CAR T-cells evaluated by the number of therapeutic products generated · Feasibility of adequate leucapheresis collection and generation of CD19CAR T-cells as evaluated by the number of therapeutic products generated. · 28 days
次要终点：Response at 1 and 3 months；Frequency of circulating CD19CAR T-cells in peripheral blood；Incidence of B-cell aplasia；Relapse rate at 1 and 2 years；Progression Free Survival (PFS) at 1 and 2 years；Overall Survival (OS) at 1 and 2 years
接受先进治疗研究药品（ATIMP）：CD19 CAR-T细胞治疗。
CAROUSEL试验是一项单中心、非随机、开放标签I期临床试验，研究一种先进治疗研究药品（ATIMP），对象为年龄≥16岁的复发/难治性原发性中枢神经系统淋巴瘤患者。研究将评估ATIMP的制备可行性、CD19 CAR-T细胞治疗的安全性，以及给药后CAR-T细胞在患者体内的植入、扩增和持续存在情况。
The CAROUSEL Trial is a single-centre, non-randomised, open label Phase I clinical trial of an Advanced Therapy Investigational Medicinal Product (ATIMP) in adults (age ≥16) with relapsed/refractory Primary CNS Lymphoma. The study will evaluate the feasibility of generating the ATIMP, the safety of administering CD19CAR T-cell therapy and how effectively CD19CAR T-cells engraft, expand and persist following administration in patients with relapsed/refractory primary CNS lymphoma.
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