肿瘤细胞治疗研究
英文原题：A Pediatric and Young Adult Trial of Genetically Modified T Cells Directed Against CD19 for Relapsed/Refractory CD19+ Leukemia
这是一项 I/II 期注册临床试验，评估 CD19CAR-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 167 例。试验地点：美国 · 洛杉矶、奥克兰、西雅图（共 3 个中心）。登记号：NCT02028455。
不限性别 · ≥ 1 Year 且 ≤ 26 Years
纳入标准： 患者入组时须年龄≥12个月且<27岁。 体重须≥10 kg。 经确认的CD19阳性白血病复发：异基因HCT后骨髓疾病比例≥0.01%，或出现孤立性髓外疾病。（注：目前已停止白血病患者入组。） 或者 既往未接受异基因HCT，且符合以下至少一项： * 第二次或后续复发，可伴或不伴髓外疾病（孤立性髓外疾病也可入组）。 * 再诱导治疗第1个月末首次骨髓复发，骨髓原始细胞疾病比例≥0.01%，可伴或不伴髓外疾病。 * 原发难治，定义为诱导治疗后骨髓为M2或M3。 * 有HCT指征，但被判定不适合接受HCT。 或者 CD19阳性非霍奇金淋巴瘤（NHL）难治或复发，且无已知可治愈疗法。（注：淋巴瘤患者仍可入组。） 中枢神经系统（CNS）受累患者可入组，前提是无症状，且研究主要研究者认为从入组至T细胞输注期间可合理控制疾病负荷。出现显著神经功能恶化的患者，在其他治疗使神经功能稳定前不得接受T细胞输注。 * Lansky体能状态评分≥50；年龄≥16岁者Karnofsky评分≥50。 * 预期寿命>8周。 * 无活动性GVHD，且入组前4周未接受GVHD免疫抑制治疗。 * 已从既往所有化疗、免疫治疗或放疗的急性毒性反应中恢复。 * 距末次化疗至少7天（不包括鞘内化疗或维持化疗）。 * 入组前7天内未使用全身性皮质类固醇（生理替代剂量除外）。 * 不允许既往接受仍可检测到的基因改造细胞治疗或病毒治疗。 * 按年龄和性别，血清肌酐正常。 * 总胆红素<ULN的3倍，或结合胆红素<2 mg/dL。 * ALT<ULN的5倍。 * 超声心动图（ECHO）缩短分数（SF）>28%，或多门控采集扫描（MUGA）射血分数（EF）>50%。 * 绝对淋巴细胞计数（ALC）≥100个/μL。 * 室内空气下脉搏血氧饱和度≥90%。 入组前3个月内须有记录证实患者HIV抗原及抗体、乙肝表面抗原和丙肝抗体检测均为阴性。丙肝抗体阳性者须记录PCR检测阴性方可入组。 不得存在活动性且具有临床意义的CNS功能障碍，包括但不限于未控制的癫痫、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。 须同意在T细胞输注期间及输注后12个月内使用高效避孕措施。 患者必须能够耐受单采程序，包括必要时置入临时单采导管。 除CD19阳性白血病外，不得有其他活动性恶性肿瘤。 不得有活动性重度感染，定义为： * 入组前48小时内血培养阳性； * 入组前48小时内体温>38.2°C且有感染临床体征。 不得存在主要研究者或其指定人员认为会妨碍患者接受方案治疗的任何并发疾病。原发性免疫缺陷/骨髓衰竭综合征患者排除。 研究参与者或其父母/法定监护人须同意参加最长15年的长期随访，前提是受试者已入组并接受T细胞输注。
Inclusion Criteria: Patients must be ≥12 months of age and \<27 years of age at the time of study enrollment. Must be ≥10kg Confirmed CD19+ leukemia recurrence defined as ≥0.01% disease in the marrow or isolated extramedullary disease following allogeneic HCT. \[N.B. Study closed to enrollment of leukemia subjects\] OR No prior history of allogeneic HCT (one of the following) * 2nd or greater relapse, with or without extramedullary disease (isolated extramedullary disease is eligible) * 1st marrow relapse at end of 1st month of re-induction with marrow having ≥0.01% blast disease, with or without extramedullary disease * Primary Refractory as defined as having M2 or M3 marrow after induction * Subject has indication for HCT but has been deemed ineligible OR CD19+ Non-Hodgkin Lymphoma (NHL) refractory or relapsed with no known curative therapies available \[N.B. Study remains open to enrollment of lymphoma subjects\] Patients with CNS involvement are eligible provided that they are asymptomatic and in the opinion of the study PI have a reasonable expectation that disease burden can be controlled in the interval between enrollment and T cell infusion. Patients that have a significant neurologic deterioration will be not be eligible for T cell infusion until alternate therapies result in neurological stabilization. Patients must have a Lansky performance status score of ≥50 or a Karnofsky score of ≥ 50 for patients ≥16 years of age. Life Expectancy of \>8 weeks Patients must be free from active GVHD and off immunosuppressive GVHD therapy for 4 weeks prior to enrollment. Recovered from acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy It must be at least 7 days since last chemotherapy was administered (this does not include intrathecal chemotherapy or maintenance chemotherapy) No systemic corticosteroids (unless physiologic replacement dosing) within 7 days of enrollment. No prior genetically modified cell therapy that is still detectable or virotherapy allowed. * Normal serum creatinine based on age/gender * Total bilirubin \</3x ULN OR conjugated bilirubin \</2mg/dl * ALT \</5X ULN * SF of \>28% by ECHO or EF \>50% by MUGA * ALC of \>/= 100 cells/ul * Pulse ox \>/= 90% on room air Patient must have documented negative HIV antigen and antibody, Hepatitis B surface antigen, and Hepatitis C antibody within 3 months prior to enrollment. For patient with positive Hepatitis C Ab, negative PCR testing must be documented in order to be eligible. Patients must NOT have active clinically significant CNS dysfunction (including but not limited to such as uncontrolled seizure disorder, paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injuries, dementia, cerebellar disease, organic brain syndrome, psychosis, coordination or movement disorder) Must agree to highly effective contraception during and for 12 months after T cell infusion. Patients must be able to tolerate apheresis procedure, including placement of temporary apheresis line if required. Patients must NOT have an active malignancy other than CD19+ leukemia. Patients must NOT have an active severe infection defined as: * A positive blood culture within 48 hours of study enrollment * A fever above 38.2 C AND clinical signs of infection within 48 hours of study enrollment Patients must NOT have any concurrent medical condition that, in the opinion of the PI or designee, would prevent the patient from undergoing protocol-based therapy. Patients with a primary immunodeficiency/ bone marrow failure syndrome are excluded from this trial. Research participant or parent/legal guardian must agree to participate in long-term follow-up for up to 15 years, if they are enrolled in the study and receive T-cell infusion.
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 Participants Who Experienced an Adverse Event Meeting the Dose-Limiting Toxicity Definition · The safety of the T cell infusion at the maximum tolerated dose determined in Phase 1, and further characterized in Phase 2, will be described · Initial CAR T cell infusion through 30 days post infusion；Number of Participants With an MRD Negative Complete Remission After Initial CAR T Cell Infusion · The efficacy of the T cell infusion will be estimated based on the number of participants who have an MRD negative bone marrow aspirate following the initial T cell infusion · Initial CAR T cell infusion through Day 63 post infusion assessment (+/- 14 days)；Number of Participants Who Have a Releasable Cell Product Generated · The feasibility of manufacturing and releasing T cell products from pediatric and young adult patients with CD19+ relapsed or refractory leukemia · Up to 28 days per manufacturing attempt
次要终点：Persistence of Functional CD19 CAR+ T Cells；Number of Participants With Recrudescence or Development of Acute GVHD (Graft Versus Host Disease) Symptoms Post CAR T Infusion；Number of Participants That Received Cetuximab Who Have T Cells Successfully Ablated
本I期队列接受患者来源的CD19特异性CAR T细胞，剂量为5×10^5个CAR T细胞/kg。
本I期队列接受患者来源的CD19特异性CAR T细胞，剂量为1×10^6个CAR T细胞/kg。
本I期队列接受患者来源的CD19特异性CAR T细胞，剂量为5×10^6个CAR T细胞/kg。
本I期队列接受患者来源的CD19特异性CAR T细胞，剂量为1×10^7个CAR T细胞/kg。
在按方案使用氟达拉滨和环磷酰胺进行淋巴细胞清除后，本I期队列接受患者来源的CD19特异性CAR T细胞，剂量为5×10^5个CAR T细胞/kg。
在按方案使用氟达拉滨和环磷酰胺进行淋巴细胞清除后，本I期队列接受患者来源的CD19特异性CAR T细胞，剂量为1×10^6个CAR T细胞/kg。
本II期队列接受患者来源的CD19特异性CAR T细胞，剂量为1×10^6个CAR T细胞/kg；如有指征，输注前进行淋巴清除。
复发或难治性白血病患者常会对化疗产生耐药。因此，本研究尝试直接从患者体内获取T细胞，并通过基因改造使其表达嵌合抗原受体（CAR）。CAR可使T细胞识别并杀伤白血病细胞：CD19阳性白血病患者的白血病细胞表面表达CD19蛋白。本I/II期研究旨在确定CAR阳性T细胞的最大耐受剂量并评估疗效。I期队列仅纳入既往接受过异基因造血细胞移植（HCT）的患者；II期队列则不要求既往接受过HCT。
Patients with relapsed or refractory leukemia often develop resistance to chemotherapy. For this reason, we are attempting to use T cells obtained directly from the patient, which can be genetically modified to express a chimeric antigen receptor (CAR). The CAR enables the T cell to recognize and kill the leukemic cell through the recognition of CD19, a protein expressed of the surface of the leukemic cell in patients with CD19+ leukemia. This is a phase 1/2 study designed to determine the maximum tolerated dose of the CAR+ T cells as well as to determine the efficacy. The phase 1 cohort is restricted to those patients who have already had an allogeneic hematopoietic cell transplant (HCT). The phase 2 is open to all patients regardless of having a history of HCT.
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