肿瘤细胞治疗研究
英文原题：HA-1 T TCR T Cell Immunotherapy for the Treatment of Patients With Relapsed or Refractory Acute Leukemia After Donor Stem Cell Transplant
这是一项 I 期注册临床试验，评估 T 细胞治疗白血病、急性淋巴细胞白血病、急性髓系白血病的安全性、可行性及初步疗效。当前状态：招募中。计划入组 24 例。试验地点：美国 · 西雅图（共 1 个中心）。登记号：NCT03326921。
不限性别 · ≤ 80 Years
纳入标准：
* 入组时年龄0–80岁。
* 受试者须表达HLA-A*0201。
* 受试者须具有HA-1(H)基因型（RS_1801284：A/G或A/A）。
* 受试者须有一名成年造血干细胞移植（HCT）供者，按机构标准达到充分HLA匹配（包括HLA相合的亲属或无关供者，以及HLA不相合的家庭供者，包括单倍体相合供者），且符合以下之一：
* HLA-A*0201阳性且HA-1(H)阴性（RS_1801284：G/G）；或
* HLA-A*0201阴性。
* 目前正在接受或既往接受过异基因HCT，适应证为以下任一疾病：
* 任一亚型急性髓系白血病（AML）；
* 任一亚型急性淋巴细胞白血病（ALL）；
* 混合表型/未分化型/其他类型急性白血病，包括母细胞性浆细胞样树突状细胞肿瘤；
* 有急变期病史的慢性髓性白血病，且符合以下情况之一：
* HCT后任何时间复发或难治（骨髓原始细胞≥5%，或外周血可见原始细胞）；
* 微小残留病（MRD）持续升高（定义为形态学、流式细胞术、分子或细胞遗传学检测可检出疾病，但形态学骨髓原始细胞<5%，且连续两次检测中至少两次均无循环原始细胞），并且HCT后任何时间对酪氨酸激酶抑制剂治疗难治或不适合接受此类治疗；
* 任一亚型骨髓增生异常综合征（MDS）；
* 慢性粒单核细胞白血病（CMML）；
* 幼年型粒单核细胞白血病（JMML）。
* 受试者须能够理解并愿意提供知情同意。认知决策能力受损的成人可由其法定授权代表代为同意；未满18岁的受试者须由父母或法定代表同意。
* 若已入组并接受T细胞输注，受试者须同意参加最长15年的长期随访。
* HCT后复发或MRD阳性的受试者可接受其他疾病治疗药物，且仍符合本方案资格。
* 本方案不要求特定体能状态评分；体能状态较差者可能需要延迟输注HA-1 TCR T细胞。
供者选择纳入标准：
* 供者年龄≥18岁。
* 供者须能够提供知情同意。
排除标准：
* 主要研究者（PI）酌情判断，存在使受试者不适合接受细胞治疗的医学或心理状况。
* 有生育能力且不愿在治疗期间及治疗后12个月内采取避孕措施的受试者。
* 除白血病外的合并疾病导致预期寿命<3个月。
* 最近一次移植后仍有持续的4级急性GVHD或重度慢性GVHD。例外：若GVHD诊断存在疑问和/或严重程度持续显著改善，PI可逐案酌情允许受试者入组。
* 器官毒性不一定导致排除，PI可酌情决定；但可能需要延迟输注HA-1 TCR T细胞。
供者选择排除标准：
* HIV-1、HIV-2、人T淋巴细胞病毒（HTLV）-1或HTLV-2血清阳性，或存在活动性乙肝/丙肝病毒感染的供者。
* 居住在美国境外的无关供者，除非供者筛查、检测及白细胞单采均在国家骨髓供者计划（NMDP）关联且合格的供者中心进行，并由NMDP协调。
Inclusion Criteria:
* Subject age 0-80 years at the time of enrollment.
* Subject must express HLA-A\*0201
* Subject must have the HA-1(H) genotype (RS\_1801284: A/G, A/A)
* Subject must have an adult donor for HCT who is adequately HLA matched by institutional standards (includes HLA-matched related or unrelated donors, and HLA-mismatched family donors, including haploidentical donors) and is either:
* HLA-A\*0201 positive and HA-1(H) negative (RS\_1801284: G/G) or
* HLA-A\*0201 negative
* Subjects who are currently undergoing or who previously underwent allogeneic HCT for
* Acute myeloid leukemia (AML) of any subtype
* Acute lymphoid leukemia (ALL) of any subtype
* Mixed phenotype/undifferentiated/any other type of acute leukemia, including blastic plasmacytoid dendritic cell neoplasm
* Chronic myeloid leukemia with a history of blast crisis and:
* With relapse or refractory disease (\>= 5% marrow blasts, or circulating blasts) at any time after HCT
* With persistent rising minimal residual disease (defined as detectable disease by morphology, flow cytometry, molecular or cytogenetic testing but \< 5% marrow blasts by morphology, no circulating blasts on \>= 2 of two consecutive tests), refractory or ineligible for treatment with tyrosine kinase inhibitors at any time after HCT
* Myelodysplastic syndrome (MDS) of any subtype
* Chronic myelomonocytic leukemia (CMML)
* Juvenile myelomonocytic leukemia (JMML)
* Subjects must be able to understand and be willing to give informed consent; decision-impaired adults may consent with their legally authorized representative; parent or legal representative will be asked to consent for subjects younger than 18 years old
* Subjects 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
* Subjects who have relapsed or have MRD after HCT may receive other agents for treatment of disease and remain eligible for the protocol
* A specific performance status score is not required for enrolling on the protocol; a delay in infusion of the HA-1 TCR T cells may be required for subjects with low performance status
DONOR SELECTION INCLUSION
* Donor age \>= 18 years
* Donors must be able to give informed consent
Exclusion Criteria:
* Medical or psychological conditions that would make the subject unsuitable candidate for cell therapy at the discretion of the principal investigator (PI)
* Fertile subjects unwilling to use contraception during and for 12 months after treatment
* Subjects with a life expectancy of \< 3 months of enrollment from coexisting disease other than leukemia
* Subjects who have ongoing grade IV acute GVHD or severe chronic GVHD following most recent transplant. Exception: the principal investigator (PI) may make an exception on a case-by-case basis to include such a subject if there is doubt surrounding the GVHD diagnosis and/or sustained significant improvement in GVHD severity
* The presence of organ toxicities will not necessarily exclude subjects from enrolling on the protocol at the discretion of the PI; however, a delay in the infusion of HA-1 TCR T cells may be required
DONOR SELECTION EXCLUSION
* Donors who are 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
* Unrelated donor residing outside of the United States of America (USA) unless the donor screening, testing and leukapheresis occur at an National Marrow Donor Program (NMDP)-affiliated and qualified donor center and are facilitated by the NMDP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：Feasibility of manufacturing minor H antigen (HA-1) T cell receptor (TCR) CD8+ and CD4+ T cells · Proportion of subjects for whom a HA-1 TCR T cell product can be produced. · At time of T cell infusion (at day 0)；Feasibility of administering minor H antigen (HA-1) T cell receptor (TCR) CD8+ and CD4+ T cells · Proportion of subjects for whom a HA-1 TCR T cell product can be administered. · At time of T cell infusion (at day 0)；Incidence of dose-limiting toxicities of HA-1 T cell receptor (TCR) T cells · Toxicities will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4. · Up to 12 weeks after T-cell infusion
次要终点：Duration of in vivo persistence of transferred HA-1 T cell receptor (TCR) CD4+ T cells in peripheral blood；Duration of in vivo persistence of transferred HA-1 T cell receptor (TCR) CD8+ T cells in peripheral blood；Presence, proportion and persistence of HA-1 T cell receptor (TCR) CD4+ T cells in the bone marrow；Presence, proportion and persistence of HA-1 T cell receptor (TCR) CD8+ T cells in the bone marrow；Specific cytolytic activity of HA-1 T cell receptor (TCR) CD8+ and CD4+ T cells against HLA-A*0201+ HA-1+ target cells before adoptive T cell transfer；Specific cytolytic activity of HA-1 T cell receptor (TCR) CD8+ and CD4+ T cells against HLA-A*0201+ HA-1+ target cells after adoptive T cell transfer；Reduction of leukemia in the bone marrow in subjects who have measurable leukemia in the marrow prior to HA-1 T cell receptor (TCR) T cell infusion；Reduction of recipient normal hematopoietic cells in the bone marrow in subjects who have measurable recipient normal hematopoietic cells in the marrow prior to HA-1 T cell receptor (TCR) T cell infusion
患者接受淋巴清除化疗，例如方案规定的氟达拉滨和环磷酰胺或减瘤方案；疗程结束后2–14天给予HA-1 TCR T细胞。随后静脉输注CD4+和CD8+ HA-1 TCR T细胞。
这项I期试验研究CD4+和CD8+ HA-1 T细胞受体（TCR）T细胞（HA-1 T TCR T细胞）的副作用和最佳剂量，治疗供者干细胞移植后持续存在、复发或对治疗无应答的急性白血病患者。T细胞受体是T细胞表面的一种特殊蛋白，帮助T细胞识别其他细胞（包括白血病细胞）上的蛋白。HA-1是一种存在于部分人血细胞表面（包括白血病细胞表面）的蛋白。HA-1 T细胞免疫疗法通过向供者细胞导入基因，使其能够识别白血病细胞上的HA-1标志物。
This phase I trial studies the side effects and best dose of CD4+ and CD8+ HA-1 T cell receptor (TCR) (HA-1 T TCR) T cells in treating patients with acute leukemia that persists, has come back (recurrent) or does not respond to treatment (refractory) following donor stem cell transplant. T cell receptor is a special protein on T cells that helps them recognize proteins on other cells including leukemia. HA-1 is a protein that is present on the surface of some peoples' blood cells, including leukemia. HA-1 T cell immunotherapy enables genes to be added to the donor cells to make them recognize HA-1 markers on leukemia cells.
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