肿瘤细胞治疗研究
英文原题：CD22 CAR T-cells to Extend Remission Following Commercial CD19 CAR T-cells in Children, Adolescents, and Adults With Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia
这是一项 II 期注册临床试验，评估 CD22T 细胞治疗急性淋巴细胞白血病的安全性、可行性及初步疗效。当前状态：招募中。计划入组 20 例。试验地点：美国 · 贝塞斯达（共 1 个中心）。登记号：NCT07328503。
不限性别 · ≥ 3 Years 且 ≤ 65 Years
纳入标准：
* 受试者须具备病理学诊断证明，确诊为复发/难治性B细胞急性淋巴细胞白血病（ALL）。
* 诊断时或复发时，恶性细胞曾表达CD19和CD22。
* 年龄≥3岁且≤65岁。
* 受试者须在白细胞单采前≥2个月且≤7个月内接受过美国食品药品监督管理局（FDA）批准的CD19 CAR-T细胞产品治疗B细胞ALL；若本方案不进行白细胞单采，则以淋巴清除（LD）治疗为参照。
* 筛选时流式细胞术显示处于微小残留病（MRD）阴性缓解。
* 不适合接受或不愿接受异基因干细胞移植（SCT）。
* 临床体能状态（PS）：≥16岁受试者的Karnofsky评分≥50%；<16岁受试者的Lansky评分≥50%。因瘫痪而无法行走、但能在轮椅上保持直立的受试者也可考虑入组。
* 筛选时既往CAR-T细胞输注相关的细胞因子释放综合征（CRS）和/或免疫效应细胞相关神经毒性综合征（ICANS）已无持续表现。
* 受试者须具有足够的器官功能，具体如下：
* 总胆红素≤机构正常值上限（ULN）的2倍；
* 天冬氨酸氨基转移酶（AST）≤ULN的10倍；
* 丙氨酸氨基转移酶（ALT）≤ULN的10倍；
* 肌酐≤下列相应年龄上限；若肌酐高于上限，则实测肌酐清除率须≥60 mL/min/1.73 m²：
* 年龄≤5岁：血清肌酐≤0.8 mg/dL；
* 年龄>5岁且≤10岁：血清肌酐≤1.0 mg/dL；
* 年龄>10岁：血清肌酐≤1.2 mg/dL。
* 允许受试者仍有任何级别的CAR-T细胞相关血细胞减少。
* 心功能：左心室射血分数≥45%，或短轴缩短率≥28%。
* 肺功能：室内空气下基线血氧饱和度≥92%；有呼吸道症状（如呼吸困难、低氧，血氧饱和度<92%）的受试者，调整后的肺一氧化碳弥散量（DLCO）须>45%。
* 有生育能力的女性（WOCBP）须同意从入组时起至末次联合化疗后12个月采取高效避孕措施（激素避孕、宫内节育器[IUD]、禁欲或手术绝育）。
注：WOCBP指已初潮、未成功接受手术绝育且未绝经的任何个体。
有生育能力的男性须同意从入组时起至末次研究药物给药后7个月采取有效避孕措施（屏障避孕、手术绝育或禁欲）。还建议其伴侣采取高效避孕措施（激素避孕、IUD或手术绝育）。有生育能力的个体在同一期间不得冷冻或捐献精子。
* 哺乳期受试者须愿意从开始研究治疗至末次研究药物给药后6个月停止哺乳。
* 受试者须同时参加方案15-C-0028“参加儿科肿瘤分支临床试验后基因治疗相关迟发不良事件随访评估”。
* 受试者本人或其法定授权代表（LAR）能够理解并愿意签署书面知情同意文件。
排除标准：
* 存在任何中枢神经系统（CNS）受累或中枢神经系统以外的髓外病变迹象。
* 既往接受造血干细胞移植（HSCT）的受试者存在任何活动性移植物抗宿主病（GVHD）。
* CD19 CAR-T治疗后疾病复发且需要治疗。注：允许为维持缓解而在CD19 CAR-T治疗后接受维持治疗（如长春新碱或酪氨酸激酶抑制剂），但须在白细胞单采或LD前洗脱1周；若本方案不进行白细胞单采，则以LD治疗为参照。
* 白细胞单采或LD前1周内使用过任何研究性药物；若本方案不进行白细胞单采，则以LD治疗为参照。
* 筛选时血清或尿液β-人绒毛膜促性腺激素（β-HCG）检测证实妊娠。
* 人类免疫缺陷病毒（HIV）感染，即HIV抗体血清学阳性。
* 乙型肝炎病毒（HBV）感染，即乙型肝炎表面抗原（HBsAg）阳性。
* 丙型肝炎病毒（HCV）感染，即丙型肝炎血清学抗体阳性。
* 曾因与本研究所用药物或细胞制备过程中所用药物具有相似化学或生物组成的化合物而发生严重的速发型超敏反应。
* 根据病史、体格检查和/或实验室检查判断存在未控制的有症状并发疾病，或存在会妨碍遵守研究要求或给受试者带来不可接受风险的社会处境。
* INCLUSION CRITERIA: * Participants must have documentation of pathologic confirmation of a diagnosis of relapsed/refractory B cell acute lymphoblastic leukemia (ALL). * History of CD19 and CD22 expression on malignant cells at diagnosis or relapse. * Age between \>= 3 years and \<= 65 years * Participants must have received an FDA-approved CD19 CAR T-cell construct for treatment of B cell ALL within the time period of \>= 2 months and \<= 7 months prior to apheresis or lymphodepleting (LD) (if apheresis is not done on this protocol). * Must be in an MRD-negative remission as demonstrated by flow cytometry at screening. * Must be ineligible for or unwilling to undergo allogeneic stem cell transplant (SCT). * Clinical performance status (PS): Karnofsky \>= 50% (participants \>= 16 years of age), or Lansky scale \>= 50% (participants \< 16 years of age). Participants who are unable to walk because of paralysis, but who are upright in a wheelchair may be considered eligible. * Must have no ongoing signs of CRS from prior CAR T cell infusion and/or ICANs at screening. * Participants must have adequate organ function as defined below: * Total bilirubin \<= 2 x institutional upper limit of normal (ULN) * Aspartate Aminotransferase (AST) \<= 10 x ULN * Alanine Aminotransferase (ALT) \<= 10 x ULN * creatinine \<= the maximum for age listed below OR measured creatinine clearance \>= 60 mL/min/1.73 m\^2 for participants with creatinine levels above the max * Age: \<=5, Maximum Serum, Creatinine \<= .8 mg/dL * Age: \>5 to \<=10, Maximum Serum, Creatinine \<= 1.0mg/dL * Age: \>10, Maximum Serum, Creatinine \<= 1.2mg/dL * A participant may have continued to expect CAR T cell-associated cytopenias of any grade. * Cardiac function: left ventricular ejection fraction\>= 45% or fractional shortening \>= 28%. * Pulmonary function: baseline oxygen saturation \>= 92% on room air; participants with respiratory symptoms (e.g., dyspnea, hypoxia \<92%) must have a diffusing capacity of the lungs for carbon monoxide (DLCO)/adjusted \> 45%. * Women of childbearing potential (WOCBP) must agree to use highly effective contraception (hormonal, intrauterine device (IUD), abstinence, surgical sterilization) at the study entry and up to 12 months after the last dose of combined chemotherapy. Note: WOCBP is defined as any individual who has experienced menarche and who has not undergone successful surgical sterilization or who is not postmenopausal. Men able to father a child must agree to use an effective method of contraception (barrier, surgical sterilization, abstinence) at the study entry and up to 7 months after the last dose of study drugs. We also will recommend men ask their partners to be on highly effective birth control (hormonal, IUD, surgical sterilization). Individuals able to father a child must not freeze or donate sperm within the same period. * Nursing participants must be willing to discontinue nursing from study treatment initiation through 6 months after the last dose of the study drug(s). * Participants must be enrolled on protocol 15-C-0028, Follow-Up Evaluation for Gene- Therapy Related Delayed Adverse Events after Participation in Pediatric Oncology Branch Clinical Trials. * Ability of participant or /Legally Authorized Representative (LAR) to understand and be willing to sign a written informed consent document. EXCLUSION CRITERIA: * Any central nervous system (CNS) involvement or signs of non-CNS extramedullary disease. * Any active graft versus host disease (GVHD) in participants who are post-HSCT. * Participants with disease recurrence requiring therapy post CD19 CAR. Note: Maintenance therapy post CD19 CAR (e.g., vincristine or tyrosine kinase inhibitor) for remission maintenance is allowed and will require a 1-week washout prior to apheresis or LD (if apheresis is not done on this protocol). * Any investigational agent within 1 week before apheresis or LD (if apheresis is not done on this protocol). * Pregnancy confirmed with beta-human chorionic gonadotropin (beta-HCG) serum or urine test performed at screening. * Human immunodeficiency virus (HIV) infection, as measured by seropositivity for (HIV) antibody. * Hepatitis B virus (HBV) infection, as measured by positivity for hepatitis B surface antigen (HBsAg). * Hepatitis C virus (HCV) infection, as measured by seropositivity for hepatitis C. * History of severe, immediate hypersensitivity reaction attributed to compounds of similar chemical or biological composition to any agent used in the study or in the manufacturing of cells. * Uncontrolled, symptomatic intercurrent illness evaluated by medical history, physical exam, and/or laboratory testing, or social situation that would limit compliance with study requirements or would pose an unacceptable risk to the participant.
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：1-year RFS (recurrence free survival) · RFS of participants will be assessed by a Kaplan-Meier curve. The RFS probability and the median RFS will be reported along with 95% confidence intervals. · 1 year post cell infusion
次要终点：2-year RFS；1-year and 2-year OS (overall survival)；Short-term safety；Long-term safety；RFS from the time of additional CD22 CAR T-cell infusions
淋巴清除化疗后给予CD22 CAR-T细胞。
背景： 急性淋巴细胞白血病（ALL）是一种血液癌症。嵌合抗原受体（CAR）疗法是提取患者的免疫细胞（T细胞）并对其进行改造，使其更有效地靶向癌细胞。靶向CD19标志物的CAR-T细胞疗法已能治愈许多儿童和成人ALL患者，但约50%的患者会在一年内复发。研究人员希望了解，第二次使用靶向另一种标志物CD22的CAR-T细胞治疗，能否让癌症更长时间不复发。 目的： 评估CD22 CAR-T细胞疗法能否延长ALL患者的无病时间。 入选人群： 3至65岁、接受CD19 CAR-T细胞治疗ALL后未发现癌症迹象的人群。 研究设计： 受试者将接受筛选、影像学检查和心功能检查，并采集骨髓组织样本（活检）及脊髓周围液体样本。 受试者将通过称为白细胞单采的程序采集白细胞（T细胞）：血液经静脉引出，通过机器分离T细胞，再经另一静脉将其余血液回输体内。随后在实验室改造这些细胞，制备CD22 CAR-T细胞疗法。 受试者将连续4天服药，为CAR-T细胞治疗做好准备；之后通过置入静脉的导管输注改造后的T细胞。部分受试者治疗期间可能需要住院。 受试者将接受为期2年的随访。
Background: Acute lymphoblastic leukemia (ALL) is a type of blood cancer. Chimeric antigen receptor (CAR) therapy involves taking immune cells (T cells) from a person and modifying them to better target cancer cells. CAR T-cell therapy that targets a marker called CD19 has been show to can cure ALL in many children and adults. But in about 50% of patients, the ALL comes back within a year. Researchers want to find out if a second treatment with CAR T-cell therapy that targets a different marker, CD22, can keep the cancer away longer. Objective: To see if CD22 CAR T-cell therapy can keep ALL away longer. Eligibility: People aged 3 to 65 years who have no signs of cancer after CD19 CAR T-cell treatment for ALL. Design: Participants will be screened. They will have imaging scans and tests of their heart function. A sample of tissue (biopsy) will be collected from their bone marrow. They will have a fluid sample collected from the area around their spinal cord. Participants will undergo collection of their white blood cells (T cells) during a procedure called leukapheresis. Blood will be taken from their body through a vein. The blood will pass through a machine that separates out the T cells. The remaining blood will be returned to the body through a different vein. The cells will be altered in a lab to create CD22 CAR T-cell therapy. Participants will take drugs over 4 consecutive days to prepare their body for the CAR T-cell therapy; then they will receive their modified T cells through a tube inserted into a vein. Some people may need to stay in the hospital during treatment. Participants will have follow-up visits for 2 years.
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