肿瘤细胞治疗研究
英文原题：A Feasibility and Safety Study of Dual Specificity CD19 and CD22 CAR-T Cell Immunotherapy for CD19+CD22+ Leukemia
这是一项 I 期注册临床试验，评估 CD19 细胞治疗用于白血病、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 78 例。试验地点：美国 · 洛杉矶、华盛顿特区、印第安纳波利斯、西雅图（共 5 个中心）。登记号：NCT03330691。
不限性别 · ≤ 30 Years
纳入标准
• 前2名受试者：男性或女性，年龄≥18岁且<27岁（截至2018年2月16日，前2名受试者已完成入组和治疗）；后续受试者年龄<31岁。
• 确诊CD19阳性、CD22阳性白血病。
• 疾病状态符合以下条件之一：
• 既往接受异基因造血细胞移植（HCT）：确认CD19阳性、CD22阳性白血病复发，即异基因HCT后疾病比例至少为0.01%；
• 复发／难治性且既往未接受异基因HCT，符合以下任一项：
• 骨髓第二次或以上复发，可伴或不伴髓外疾病；
• 首次骨髓复发发生于一线治疗结束后第1个月，或再诱导治疗后骨髓形态学和／或多参数流式（MPF）检测原始细胞≥0.01%；
• 原发难治，定义为至少接受2种不同诱导方案后，多参数流式检测原始细胞>5%；
• 受试者有HCT指征但被判定不适合移植，包括移植前MRD持续阳性。
• 如存在CNS受累，应无症状；主要研究者认为从入组到T细胞输注期间可合理控制疾病负荷。发生显著神经系统恶化的受试者，在病情稳定前不符合T细胞输注条件。
• 入组前4周内无活动性GVHD，且已停用GVHD免疫抑制治疗。
• Lansky或Karnofsky体能状态评分≥50分。
• 预期寿命≥8周。
• 已从既往化疗、免疫治疗和放疗的急性毒性中恢复。
• 末次化疗后至少7天（鞘内维持化疗除外）。
• 末次全身糖皮质激素给药后至少7天（生理替代剂量除外）。
• 无既往仍可检测到的基因修饰细胞治疗或病毒治疗。
• 器官功能符合要求。
• 实验室检查指标符合要求。
• 愿意参加最长15年的长期随访（限入组并接受T细胞输注的患者）。
• 有生育能力／可能使他人受孕的患者须同意从首次T细胞输注起至末次T细胞输注后12个月内使用高效避孕措施。
排除标准
• 存在活动性且具有临床显著性的CNS功能障碍。
• 妊娠或哺乳期。
• 无法耐受白细胞单采。
• 除CD19阳性、CD22阳性白血病外，存在活动性恶性肿瘤。
• 存在活动性重症感染。
• 存在任何合并疾病，且主要研究者认为该病会妨碍患者接受方案规定治疗。
Inclusion Criteria: * First 2 subjects: male and female subjects age ≥18 and \< 27 years (as of 2/16/18 the first 2 subjects were enrolled and treated); subsequent subjects \<31 years. * Diagnosis of CD19+22+ leukemia * Disease status: * If post allogeneic HCT: Confirmed CD19+CD22+ leukemia recurrence defined as at least 0.01% disease following allogeneic HCT * If relapse/refractory status with no prior history of allogeneic HCT, one of the following: * Second or greater marrow relapse, with or without extramedullary disease * First marrow relapse at end of first month or re-induction with marrow having at least 0.01 % blasts by morphology and/or MPF * Primary refractory as defined as greater than 5% blasts by multi-parameter flow after at least 2 separate induction regimens. * Subject has indication for HCT but has been deemed ineligible, inclusive of persistent MRD prior to HCT * Asymptomatic from CNS involvement, if present, and in the opinion of the Principal Investigator with a reasonable expectation that disease burden can be controlled in the interval between enrollment and T-cell infusion. Subjects with significant neurologic deterioration will not be eligible for T-cell infusion until stabilized. * Free from active GVHD and off immunosuppressive GVHD therapy for 4 weeks prior to enrollment * Lansky or Karnofsky performance score of at least 50 * Life expectancy of at least 8 weeks * Recovered from acute toxic effects of all prior chemotherapy, immunotherapy, and radiotherapy * At least 7 days post last chemotherapy administration (excluding intrathecal maintenance chemotherapy) * At least 7 das post last systemic corticosteroids administration (unless physiologic replacement dosing) * No prior genetically modified cell therapy that is still detectable or virotherapy * Adequate organ function * Adequate laboratory values * Willing to participate in long-term follow-up for up to 15 years, if enrolled in the study and receive T cell infusion * Patients of childbearing/fathering potential must agree to use highly effective contraception from the time of initial T cell infusion through 12 months following the last T cell infusion Exclusion Criteria: * Presence of active clinically significant CNS dysfunction * Pregnant or breast-feeding * Unable to tolerate apheresis procedure * Presence of active malignancy other than CD19+CD22+ leukemia * Presence of active severe infection * Presence of any concurrent medical condition that, in the opinion of the Principal Investigator, would prevent the patient from undergoing protocol-specified therapy
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：The adverse events associated with one or multiple CAR T-cell product infusions will be assessed · Type, frequency, severity, and duration of adverse events will be summarized · 30 days；The number of successfully and unsuccessfully manufactured and infused CAR T-cell products will be assessed · Proportion of products successfully manufactured and infused · 28 days
患者来源的CD19特异性CAR（同时表达HER2t）及CD22特异性CAR-T细胞（同时表达EGFRt）。
患者来源的CD19特异性CAR（同时表达HER2t）及CD22特异性CAR-T细胞（同时表达EGFRt）。
复发或难治性白血病患者常对化疗产生耐药；部分患者在接受靶向CD19治疗后复发时，白血病细胞已不再表达CD19。因此，研究者尝试使用直接从患者体内获取的T细胞，并通过基因修饰使其表达两种嵌合抗原受体（CAR）：一种识别CD19，另一种识别CD22。这两种蛋白均表达于CD19阳性、CD22阳性白血病患者的白血病细胞表面。CAR使T细胞能够识别CD19和CD22并杀伤白血病细胞。本Ⅰ期研究旨在评估CAR阳性T细胞的安全性，以及能否制备足够数量的细胞用于治疗CD19阳性、CD22阳性白血病患者。
Patients with relapsed or refractory leukemia often develop resistance to chemotherapy and some patients who relapse following CD19 directed therapy relapse with CD19 negative leukemia. For this reason, the investigators are attempting to use T-cells obtained directly from the patient, which can be genetically modified to express two chimeric antigen receptors (CARs). One is to recognize CD19 and the other is to recognize CD22, both of which are proteins expressed on the surface of the leukemic cell in patients with CD19+CD22+ leukemia. The CAR enables the T-cell to recognize and kill the leukemic cell through recognition of CD19 and CD22. This is a phase 1 study designed to determine the safety of the CAR+ T-cells and the feasibility of making enough to treat patients with CD19+CD22+ leukemia.
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