肿瘤细胞治疗研究
英文原题：A Pediatric Trial of Genetically Modified Autologous T Cells Directed Against CD19 for Relapsed CD19+ Acute Lymphoblastic Leukemia
A Pediatric Trial of Genetically Modified Autologous T Cells Directed Against CD19 for Relapsed CD19+ Acute Lymphoblastic Leukemia
分数与星级只用于站内排序 —— 不代表疗效、安全性或个人适用性。
这是一项 I 期注册临床试验，评估自体 T 细胞治疗白血病的安全性、可行性及初步疗效。当前状态：进行中（不再招募）。计划入组 6 例。试验地点：美国 · 西雅图（共 1 个中心）。登记号：NCT01683279。
不限性别 · ≥ 1 Year 且 ≤ 26 Years
纳入标准： • CD19阳性白血病，首次骨髓复发且再诱导第1个月末MRD阳性。 • CD19阳性白血病，第二次或以上复发。 • CD19阳性白血病，有HCT指征但存在禁忌证。 • 年龄1至26岁。 • Karnofsky评分>50或Lansky评分>50。 • 预期生存期>12周。 • 能耐受采血，采血量为4至6 mL/kg。 • 已从既往化疗、免疫治疗或放疗的急性毒性中恢复。 • 体重大于20 kg者绝对淋巴细胞计数≥500个/mm³；其他受试者≥750个/mm³。 • 肌酐清除率或放射性核素GFR≥70 mL/min/1.73 m²，或血清肌酐符合相应年龄/性别正常值。 • 总胆红素≤正常值上限的1.5倍，或直接胆红素≤1.5 mg/dL。 • ALT≤正常值上限的3倍。 • 心电图校正QT间期<450 ms。 • 超声心动图缩短分数>28%，或MUGA测得射血分数>50%。 • HIV、乙肝和丙肝检测记录为阴性。 • 如接受T细胞输注，同意最长15年的长期随访。 排除标准： • 费城染色体阳性白血病。 • 既往接受过异基因干细胞移植。 • CNS 2级或3级。 • 既往接受过CAR修饰T细胞的细胞免疫治疗。 • 过去三个半衰期内接受过全人源化抗体。 • 入组前7天内接受全身性糖皮质激素。 • 需要补充氧气，或胸部X线显示感染过程。 • 存在中枢神经系统病变（癫痫、轻瘫、失语、脑血管缺血/出血、严重脑损伤、痴呆、小脑疾病、器质性脑综合征、精神病、协调或运动障碍）。 • 妊娠或哺乳期女性。有生育能力女性须妊娠试验阴性，并同意在T细胞输注后1年内避孕。 • 除CD19阳性白血病外存在活动性恶性肿瘤。 • 活动性严重感染，定义为入组前48小时内血培养阳性，或体温>38.2℃且入组前48小时内有感染临床体征。 • 研究方案负责人或指定人员认为会妨碍患者接受方案治疗的合并疾病。 • 21三体。 • 原发性免疫缺陷/骨髓衰竭综合征。
Inclusion Criteria: * CD19+ Leukemia in 1st marrow relapse with MRD at the end of 1st month of re-induction * CD19+ Leukemia in 2nd or greater relapse * CD19+ Leukemia with indication for HCT, but has contraindication * Age between 1 and 26 years of age * Karnofsky of \>50 or Lansky \>50 * Life Expectancy \>12 weeks * Able to tolerate a blood draw of 4-6mL/kg * Recovered from acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy * absolute lymphocyte count of \>/=750 cell/mm3 or \>/=500 is \>20kg * creatinine clearance or radioisotope GFR \>/= 70mL/min/1.73m2 OR normal serum creatinine based on age/gender * total bilirubin \</= 1.5x upper limit normal OR direct bilirubin \</= 1.5mg/dl * ALT \</= 3x upper limit normal * corrected QTc \<450msec of ECG * Shortening Fraction \>28% by ECHO or Ejection Fraction \>50% by MUGA * Documented negative HIV, Hep B and Hep C * Agree to long-term follow up for up to 15 years if they receive T cell infusion Exclusion Criteria: * Philadelphia Positive Leukemia * Prior Allogeneic Stem Cell Transplant * CNS 2 or 3 * prior cellular immunotherapy with chimeric antigen receptor modified T cells * fully humanized antibodies within three half lives * systemic corticosteroids within 7 days of enrollment * requires supplemental oxygen or has a chest X-ray with an infectious process * CNS pathology (seizure disorder, paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injuries, dementia, cerebellar disease, organic brain syndrome, psychosis, coordination or movement disorder) * Pregnant or breastfeeding women. Female participant of reproductive age must have a negative pregnancy test and agree to contraception for 1 year after T cell infusion. * Active Malignancy other than CD19+ Leukemia * Active severe infection defined as a positive blood culture within 48 hours of study enrollment or a fever \>38.2C AND clinical signs of infection within 48 hours of study enrollment * Patient has a concurrent medical condition, that in the opinion of the protocol PI or designee, would prevent the patient from undergoing protocol-based therapy. * Trisomy 21 * Primary immunodeficiency/bone marrow failure syndrome
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：Number of Participant with Adverse Events · The safety of the T cell infusion will be described and the maximum tolerated dose determined. · 42 days
次要终点：Persistence of the CD19 CAR+ T cells；Determine if there is anti-leukemic activity of the CD19 CAR+ T cells
受试者接受为期2天、总剂量3 g/m²的环磷酰胺；数日后单次输注自体CD19 CAR阳性EGFTt+T细胞。
复发性白血病患者常出现化疗耐药，因此研究者拟使用患者自身的T细胞，并通过基因修饰使其表达嵌合抗原受体（CAR）。CAR使T细胞能够识别并杀伤白血病细胞，其靶点为CD19；CD19是多数儿童ALL细胞表面表达的蛋白。本I期研究旨在确定CAR阳性T细胞的最大耐受剂量并描述治疗毒性，次要目标是观察T细胞清除患者白血病细胞的疗效。
Patients with relapsed leukemia often develop resistance to chemotherapy. For this reason, we are attempting to use a patient's own T cells, which can be genetically modified to expresses a chimeric antigen receptor(CAR). The CAR enables the T cell to recognize and kill the leukemic cells though the recognition of CD19, a protein expressed on the surface of the majority of pediatric ALL. This is a phase I study designed to determine the maximum tolerated dose of the CAR+ T cells and define the toxicity of the treatment. As a secondary aim, we will be looking at the efficacy of the T cells on eradicating the patient's leukemic cells.
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