肿瘤细胞治疗研究
英文原题：A Study of T-Cell Receptor Engineered Donor T Cells in Subjects Undergoing Allogeneic Peripheral Blood Stem Cell Transplantation
这是一项 III 期注册临床试验，评估细胞治疗用于急性髓系白血病、骨髓增生异常综合征的安全性、可行性及初步疗效。当前状态：招募中。计划入组 310 例。试验地点：美国 · 吉尔伯特、斯科茨代尔、杜阿尔特、斯坦福（共 26 个中心）。登记号：NCT07702578。
不限性别 · ≥ 18 Years
受试者纳入标准：
1. 签署知情同意书时年龄 ≥ 18 岁的患者。
2. 筛选访视时 Karnofsky 体能状态（KPS）≥ 50。
3. 接受首次 allo-HCT，诊断为：
* AML，骨髓原始细胞 < 5%，无循环原始细胞，且无髓外病变。
* MDS
4. 必须根据移植前机构 SOC 检查确定表达 HLA-A*02:01，方有资格进入治疗组。
5. 必须为 HA-2 阳性基因型，方有资格进入治疗组。
6. 接受使用半相合供者或 MMUD 的 RIC HCT。
* 治疗组受试者的供者必须为 HLA-A*02 阴性。
* 对照组受试者的供者不要求为 HLA-A*02 阴性。
7. 接受标准剂量 PTCy 用于 GvHD 预防。
8. 使用外周血干细胞来源。
9. 符合机构标准规定的移植资格器官功能参数。若器官功能可能超出机构移植标准而患者仍继续进行移植，该病例应经医学监查员（Medical Monitor）审查并批准。
10. 患者或法定授权代表（LAR）能够签署知情同意书，并愿意遵守知情同意书（ICF）和临床方案中列出的要求和限制。
11. 如果接受 TSC-101 输注，同意参与最长至 TSC-101 末次输注后 15 年的长期随访（LTFU）。
12. 男性和女性受试者的避孕措施必须符合当地关于参加临床研究者的避孕方法规定。至少应做到：
* 男性受试者必须同意在干预期间及末次 TSC-101 输注后至少 12 个月内使用高效避孕措施，并在此期间不捐献精子。
* 女性受试者如未怀孕、未哺乳，且符合以下至少一项条件，则有资格参加：
* 不是附录 2 中定义的具有生育潜力的女性（WOCBP），或
* 是 WOCBP，且同意在干预期间及末次 TSC-101 输注后至少 12 个月内遵循附录 2 中的避孕指导。
受试者排除标准：
如果患者符合以下任一标准，则被排除出研究：
1. 潜在治疗组患者的 HLA-A*02:07 为阳性。
• 考虑入对照组的患者 HLA-A*02（包括 HLA-A*02:07）可以为阳性。
2. 对于 AML 患者：处于第三次完全缓解（CR3）或以上、部分缓解、或患有活动性 AML 疾病者。
3. 如果患者在入组前 3 个月内需要血液透析或机械通气，相关情况必须与申办方医学监查员讨论。
4. 既往接受过 allo-HCT。
5. 从第 -14 天（HCT 前）至研究结束（EOS）期间使用抗胸腺细胞球蛋白（ATG）、阿仑单抗或其他体内或体外 T 细胞清除剂。在某些情况下，可能允许使用糖皮质激素和维持治疗。
6. 有对鼠源蛋白过敏的历史。
7. 同时参加使用研究性药物的另一项研究。所有其他伴随试验必须经医学监查员审查和批准。
8. 心脏疾病，定义为：
* 过去 3 个月内存在未控制或有症状的心绞痛。
* 有临床显著心律失常病史（如室性心动过速、心室颤动、尖端扭转型室性心动过速）。正在治疗中且心室率受控的心房颤动不属于排除项。
* 研究入组前 6 个月内发生心肌梗死。
* 未控制或有症状的充血性心力衰竭。
* 超声心动图或放射性核素扫描（多门控采集 [MUGA] 扫描）显示静息时心脏射血分数低于 40%，或短轴缩短率低于 22%。
9. 可能导致患者不适合参加细胞治疗试验的医疗或心理状况，包括活动性中枢神经系统疾病和/或过去 3 年内的既往恶性肿瘤，但以下情况除外：
* 允许小叶原位乳腺癌、已完全切除的皮肤基底细胞癌或鳞状细胞癌，或已治疗的宫颈原位癌。≥ 3 年前以治愈为目的治疗过的癌症将被允许
供者纳入标准：
1. 签署知情同意书时体重 ≥ 50 kg 且年龄 ≥ 16 岁的男性或女性，并符合所在机构 SOC 规定的献血标准。
2. 能够签署知情同意书，或按照机构标准操作规程（SOC）给予同意/父母同意，其中包括遵守 ICF 及本方案中列出的要求和限制。
3. 对于治疗组的供者：能够进行外周血干细胞（PBSC）采集，并至少进行 2 次白细胞单采（用于 TSC-101 生产以及用于 HCT 的干细胞采集）。
4. 对于治疗组的供者：所有 HLA-A*02 等位基因均为阴性 • 对照组受试者的供者无需 HLA-A*02 等位基因为阴性。
供者排除标准：
1. 对照组受试者的供者不符合机构供者选择标准。
2. 治疗组受试者的供者：
* 经中心实验室检测，以下任一项检测呈阳性：人类免疫缺陷病毒（HIV）-1、HIV-2、人类嗜 T 淋巴细胞病毒（HTLV）-1、HTLV-2、乙型肝炎或丙型肝炎病毒感染血清学阳性或活动性感染、梅毒、西尼罗河病毒。通过供者病史问卷筛查出克雅氏病（Creutzfeldt Jakob disease）阳性的供者也将被排除。既往有巨细胞病毒（CMV）或 EB 病毒（EBV）感染证据的供者将被允许入组。
* 经治研究者认为受试者水平的供者特异性HLA抗体高到需要采用脱敏方案治疗的情况。
Subject Inclusion Criteria:
1. Patient aged ≥ 18 years at the time of signing informed consent.
2. Karnofsky Performance Status (KPS) ≥50 at the time of the screening visit.
3. Undergoing first allo-HCT with a diagnosis of:
* AML with bone marrow blasts \< 5%, absence of circulating blasts, and absence of extramedullary disease.
* MDS
4. Must express HLA-A\*02:01 as determined by pre-transplant institutional SOC work-up to be eligible for the treatment arm.
5. Must have the HA-2 positive genotype to be eligible for the treatment arm.
6. Undergoing RIC HCT using a haplo donor or MMUD.
* Donors for treatment-arm subjects must be HLA-A\*02-negative.
* Donors for control-arm subjects do not have to be HLA-A\*02-negative.
7. Undergoing use of PTCy for GvHD prophylaxis at standard doses.
8. Use of peripheral blood stem cell source.
9. Organ function parameters for transplant eligibility are met per institutional standards. Where organ function may fall outside of institutional standard for transplant, and patient is still proceeding to transplant, the case should be reviewed and approved by the MedicalMonitor.
10. Patient or legally authorized representative (LAR) capable of giving signed informed consent and willingness to comply with the requirements and restrictions listed in the informed consent form (ICF) and clinical protocol.
11. Agrees to participate in long-term follow-up (LTFU) for up to 15 years post the final infusion of TSC-101 if they receive a TSC-101 infusion.
12. Contraceptive use by male and female subjects must be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. At a minimum:
* A male subject must agree to use a highly effective contraceptive during the intervention period and for at least 12 months after the last TSC-101 infusion and refrain from donating sperm during this period.
* A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
* Not a woman of childbearing potential (WOCBP) as defined in Appendix 2 OR
* A WOCBP who agrees to follow the contraceptive guidance in Appendix 2 during the intervention period and for at least 12 months after the last TSC-101 infusion.
Subject Exclusion Criteria:
Patients are excluded from the study if any of the following criteria apply:
1. Potential treatment-arm patient is positive for HLA-A\*02:07.
• Patients considered for the control arm can be positive for HLA-A\*02 (including HLA-A\*02:07).
2. For patients with AML: those in third complete remission (CR3) or greater, partial remission, or with active AML disease.
3. If patient required hemodialysis or mechanical ventilation within 3 months prior to enrollment, circumstances must be discussed with the Sponsor Medical Monitor.
4. Prior allo-HCT.
5. Use of anti-thymocyte globulin (ATG), alemtuzumab, or other in vivo or ex vivo T-cell depleting agents from Day -14 (pre-HCT) through end of study (EOS). Corticosteroids and maintenance therapies may be allowed under certain circumstances.
6. History of hypersensitivity to murine proteins.
7. Enrollment in a concomitant study with an investigational agent. All other concomitant trials must be reviewed and approved by the Medical Monitor.
8. Cardiac disease, defined as:
* Uncontrolled or symptomatic angina within the past 3 months.
* History of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, torsades de pointes). Atrial fibrillation with controlled ventricular response on treatment is not an exclusion.
* Myocardial infarction \< 6 months from study entry.
* Uncontrolled or symptomatic congestive heart failure.
* Cardiac ejection fraction at rest of less than 40% or shortening fraction of less than 22% by echocardiogram or radionuclide scan (multi-gated acquisition \[MUGA\] scan).
9. Medical or psychological conditions that would make the patient an unsuitable candidate for participation on a cell therapy trial, including active central nervous system disease and/or prior malignancy(s) within the last 3 years, except:
* Lobular breast carcinoma in situ, fully resected basal cell or squamous cell carcinoma of skin or treated cervical carcinoma in situ will be allowed. Cancer treated with curative intent ≥ 3 years previously will be allowed
Donor Inclusion Criteria:
1. Male or female ≥ 50 kg and aged ≥ 16 years at the time of signing informed consent who meet the criteria to donate as per the institutional SOC.
2. Capable of giving signed informed consent, or assent/parental consent per institutional SOC, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
3. For treatment-arm donors: able to undergo peripheral blood stem cell (PBSC) collection and at least 2 rounds of leukapheresis (for both TSC-101 manufacturing and the stem cell collection for HCT).
4. For treatment-arm donors: negative for all HLA-A\*02 alleles • Donors for control-arm subjects do not have to be negative for HLA-A\*02 alleles.
Donor Exclusion Criteria:
1. Donors for control-arm subjects who do not meet institutional standards for donor selection.
2. Donors for treatment-arm subjects:
* Who test positive for any of the following: human immunodeficiency virus (HIV)-1, HIV-2, human T-lymphotropic virus (HTLV)-1, HTLV-2, seropositive or with active hepatitis B or hepatitis C virus infection, syphilis, West Nile virus through central lab testing. Donors who screen positive for Creutzfeldt Jakob disease using donor history questionnaires will also be excluded. Donors with evidence of past cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infections will be allowed.
* For whom the treating Investigator deems subject level donor-specific HLA antibodies are high enough to warrant treatment with desensitization protocols.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：Relapse-free survival (RFS) · To determine the efficacy of TSC-101 by assessing relapse-free survival (RFS) · 3 years
次要终点：Event-free survival (EFS)；Overall survival (OS)；Time to relapse (TTR)；Changes over time in Quality of Life Score - EQ-5D-5L；Changes over time in Quality of Life Score - FACT-Leu；Changes over Quality of Life Scores in FACT-BMT
HLA-A*02:01阳性的受试者，接受减低强度预处理异基因造血干细胞移植，供者为HLA-A*02阴性。
1. HLA-A*02:01阴性或HA-2阴性的受试者，或符合治疗组入组条件但无法找到HLA-A*02阴性供者的受试者，将被分配至对照组，仅接受异基因造血干细胞移植（allo-HCT）。 2. HLA-A*02:01阴性的受试者将被分配至对照组，仅接受异基因造血干细胞移植（allo-HCT）。
这是一项多中心、遗传学随机、对照的3期研究，评估靶向HA-2的T细胞受体工程化供者T细胞（TSC-101）在接受减低强度预处理（RIC）造血细胞移植（HCT）的急性髓系白血病（AML）或骨髓增生异常综合征（MDS）受试者中的疗效和安全性。该研究将在接受单倍体相合或错配无关供者异基因外周血干细胞移植的受试者中，比较TSC-101联合标准治疗（SOC）与单纯SOC。
This is a multicenter, genetically-randomized, controlled, Phase 3 study evaluating the efficacy and safety of T-cell receptor-engineered donor T cells targeting HA-2 (TSC-101) administered following reduced-intensity conditioning (RIC) hematopoietic cell transplantation (HCT) in participants with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). The study will compare TSC-101 plus standard of care (SOC) versus SOC alone in participants undergoing allogeneic peripheral blood stem cell transplantation from haploidentical or mismatched unrelated donors.
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