肿瘤细胞治疗研究
英文原题：Allogeneic CD30.CAR-EBVSTs in Patients With Relapsed or Refractory CD30-Positive Lymphomas
这是一项 I 期注册临床试验，评估 T 细胞治疗淋巴瘤、霍奇金淋巴瘤的安全性、可行性及初步疗效。当前状态：进行中（不再招募）。计划入组 27 例。试验地点：美国 · 休斯顿（共 2 个中心）。登记号：NCT04288726。
不限性别 · ≥ 12 Years 且 ≤ 75 Years
纳入标准： 1. 诊断和临床病程符合以下任一类型：霍奇金淋巴瘤；侵袭性非霍奇金淋巴瘤；ALK阴性间变性T细胞淋巴瘤或其他外周T细胞淋巴瘤；ALK阳性间变性T细胞淋巴瘤。 2. 经CLIA认证的病理实验室检测证实肿瘤CD30阳性。 3. 年龄12–75岁。 4. 胆红素≤正常值上限（ULN）的2倍；Gilbert综合征患者≤3倍。 5. AST≤ULN的3倍。 6. 估算GFR>70 mL/min。 7. 室内空气下脉搏血氧饱和度>90%。 8. 心电图无显著心律失常。 9. Karnofsky或Lansky评分>60%。 10. 有可用的异基因T细胞产品，且流式细胞术测得CD30 CAR表达≥15%。 11. 既往化疗所致急性非血液学毒性均已恢复。 12. 有性生活者须愿意在研究期间及研究结束后6个月内采用较高效的避孕方法；男性伴侣应使用避孕套。 13. 已向患者或监护人说明知情同意，且其理解并签署同意书；患者或监护人已获得同意书副本。 排除标准： 1. 过去6周内接受研究性细胞治疗或疫苗。 2. 过去2周内接受研究性小分子药物。 3. 过去4周内接受抗CD30抗体治疗。 4. 过去12周内接受含吉西他滨的化疗。 5. 对含鼠源蛋白产品有超敏反应史。 6. 妊娠或哺乳期。 7. 肿瘤部位若扩大可能造成气道阻塞（由研究者酌情判断）。 8. 当前使用超过泼尼松10 mg/日等效剂量的全身性皮质类固醇。 9. 存在活动性、显著且未控制的细菌、病毒或真菌感染。 10. 有症状的心脏病（NYHA III或IV级）。
Inclusion Criteria: 1. Diagnosis and clinical course falling into one of the following categories: 1. Hodgkin lymphoma 2. Aggressive non-Hodgkin lymphoma 3. ALK-negative anaplastic T cell lymphoma or other peripheral T-cell lymphoma 4. ALK-positive anaplastic T cell lymphoma 2. CD30-positive tumor as assayed in a CLIA certified Pathology Laboratory. 3. Age 12 to 75. 4. Bilirubin 2 times (or 3 times if the patient has Gilbert syndrome) or less than the upper limit of normal. 5. AST 3 times or less than the upper limit of normal. 6. Estimated GFR \> 70 mL/min. 7. Pulse oximetry of \> 90% on room air 8. EKG shows no significant arrhythmias 9. Karnofsky or Lansky score of \> 60%. 10. Available allogeneic T cells with ≥15% expression of CD30CAR determined by flow-cytometry. 11. Recovered from all acute non-hematologic toxic effects of all prior chemotherapy. 12. Sexually active patients must be willing to utilize one of the more effective birth control methods during the study and for 6 months after the study is concluded. The male partner should use a condom. 13. Informed consent explained to, understood by and signed by patient or guardian. Patient or guardian given a copy of the informed consent form. Exclusion Criteria: 1. Received an investigational cell therapy or vaccine within the past 6 weeks. 2. Received an investigational small molecule drug within the past 2 weeks. 3. Received CD30 antibody-based therapy within the previous 4 weeks. 4. Received gemcitabine-containing chemotherapy within the previous 12 weeks 5. History of hypersensitivity reactions to murine protein-containing products. 6. Pregnant or lactating. 7. Tumor in a location where enlargement could cause airway obstruction (determined at the investigators' discretion). 8. Current use of systemic corticosteroids at a dose equivalent to higher than 10 mg/day of prednisone. 9. Active significant, uncontrolled bacterial, viral or fungal infection. 10. Symptomatic cardiac disease (NYHA Class III or IV disease).
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 rate (DLT) by CTCAE 5.0 · Any Grade 5 event, / Non-hematologic dose-limiting toxicity is any Grade 3 or Grade 4 non-hematologic toxicity that affects the cardiopulmonary system, or corresponds to neurotoxicity, or otherwise fails to return to Grade 2 within 72 hours, / Grade 2-4 allergic reaction to T-Cells, / Grade 3-4 GVHD, / Hematologic dose limiting toxicity is defined as any Grade 4 hematologic toxicity that fails to return to Grade 2 or baseline (whichever is more severe) within 14 days or within 28 days for patients with evidence of bone marrow disease. · 28 days
次要终点：Rate of Anti-Tumor effect Objective Response (OR)；Duration of response；Stable disease (SD) rate；Duration of SD；Progression free survival (PFS)
根据当前CD30 CAR-T细胞研究的安全性数据评估4个剂量水平；每个剂量水平入组3–6名患者。剂量按给药的CD30.CAR-EBVST细胞数确定，评估的总剂量水平数取决于发生的毒性。各剂量队列依次编号：剂量1为4×10⁷个细胞；剂量2为1×10⁸个；剂量3为4×10⁸个；剂量4为8×10⁸个。
本研究招募弥漫性大B细胞淋巴瘤（DLBCL）、NK/T细胞淋巴瘤及经典型霍奇金淋巴瘤（统称淋巴瘤）患者，这些患者的疾病经治疗后复发或未能缓解。目前缺乏标准治疗，或现有治疗效果不充分，因此邀请患者参加本研究。研究将检测健康供者来源的T细胞，称为EB病毒特异性T细胞（EBVST），这些细胞经实验室训练后可识别导致传染性单核细胞增多症的EB病毒。部分淋巴瘤患者的肿瘤细胞含EBV。既往将健康供者EBVST细胞系用于肿瘤细胞EBV阳性的淋巴瘤患者时，约半数患者出现缓解。细胞来自已建立的冷冻细胞库，属于“异基因”细胞（供者与患者无亲缘关系）。本研究将健康供者来源的EBV特异性T细胞改造为表达CD30.CAR的异基因CD30.CAR-EBVST，并用于CD30阳性淋巴瘤患者；若肿瘤同时表达EBV，双靶点治疗可能带来获益。研究旨在确定化疗后给予异基因CD30.CAR-EBVST治疗淋巴瘤的最高安全剂量，并评估其副作用及潜在疗效。
This study involved patients that have a cancer called diffuse large B cell lymphoma (DLBCL), NK and T cell lymphomas (NK/TL) or classical Hodgkin lymphoma (cHL) (hereafter these 3 diseases will be referred to as lymphoma). Patients lymphoma has come back or not gone away after treatment. Because there is no standard treatment for the patients cancer at this time or because the currently used treatments do not work fully in all cases, the patients are being asked to volunteer in this research study. In this study the investigators want to test a type of T cell made from a normal donor. The T cells the investigators will use are called Epstein Barr virus (EBV) specific T cells (EBVSTs) and are cells that the investigators have trained in the laboratory to recognize a EBV which is the virus that causes mono or kissing disease. Some patients with lymphoma have EBV in their cancer cells. Researchers have given T cell lines from normal donor EBVSTs to lymphoma patients who have EBV in their lymphoma cells and have seen responses in about half the patients. The cells have have been generated and are frozen in a bank. The cells are called "allogeneic" (meaning the donor is not related to the patient). CD30.CAR in EBV-specific T cells (called allogeneic CD30.CAR-EBVST) from the blood of healthy donors. The investigators are giving the cells to patients with lymphoma cells that express CD30. If the lymphoma cells also express EBV there may be some benefit from targeting both proteins. The purpose of this study is to find out the highest safe dose of allogeneic CD30.CAR-EBVST cells given following chemotherapy and used to treat lymphoma. The investigators will learn the side effects of CD30.CAR-EBVST cells in patients and see whether this therapy may help lymphoma patients
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