CLINICAL TRIAL: ADMINISTRATION OF EBV SPECIFIC CYTOTOXIC T LYMPHOCYTES TO RECIPI

临床试验：对 RECIPI 施用 EBV 特异性细胞毒性 T 淋巴细胞

基本信息

批准号：
8356760
负责人：
HELEN E HESLOP
金额：
$ 0.12万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-01 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8356760
关键词：
Adoptive Transfer Adverse effects Affect Allogenic Antigen-Presenting Cells Antigens Autologous B-Lymphocytes Blood donor Bone Marrow CD8B1 gene Cell Therapy Cells Clinical Research Clinical Trials Cytomegalovirus Cytotoxic T-Lymphocytes Development Disease EBV-Specific Cytotoxic T-Lymphocyte Epithelial Cells Frequencies Funding Generations Genetic Grant Herpesviridae Human Herpesvirus 4 Immune Immune response Immunity Immunosuppression In Vitro Incidence Infection Inflammatory Infusion procedures Interferon-alpha LMP1 Large-Cell Immunoblastic Lymphoma Lead Life Lymphocyte Lymphoproliferative Disorders Marrow Modeling National Center for Research Resources Oral Organ Patients Peripheral Population Principal Investigator Reaction Recovery Research Research Infrastructure Research Personnel Resources Risk Risk Factors Siblings Source T-Cell Depletion T-Lymphocyte Testing Therapeutic Tissues Transplantation Tumor Antigens United States National Institutes of Health Viral Antigens Virus Virus Diseases Virus Latency chemotherapy cost graft vs host disease high risk lymphoblastoid cell line neoplastic cell reconstitution response

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Epstein-Barr virus (EBV) is a latent herpes virus that infects over 90% of the population. Primary infection usually results in a mild, self-limiting illness that is followed by life-long virus latency in oral epithelial cells and in B cells. In hosts with impaired T-cell immunity, reactivation of EBV can lead to unchecked lymphoproliferation evolving to immunoblastic lymphoma. In recipients of allogeneic bone marrow from HLA-matched unrelated donors or mismatched related donors, the genetic disparity between donor and recipient results in a high risk of graft versus host disease (GvHD). In vitro T cell depletion of donor marrow effectively reduces this risk, but also delays immune recovery and increases the incidence of viral infections, including Epstein-Barr virus lymphoproliferative disease (EBV-LPD), resulting from the outgrowth of EBV transformed B cells. Risk factors for the development post-transplant of EBV-LPD are the use of marrow from a mismatched related or closely matched unrelated donor, T cell depletion of the donor marrow and intensive immunosuppression. The incidence of EBV-LPD ranges from 5% to 25% in patients with these predisposing features and responds poorly to chemotherapy or alpha interferon. Unselected populations of lymphocytes from the peripheral blood of the donor usually contain EBV-specific T cells and therefore, can be used to control EBV lymphoproliferative disease. However, the use of such therapy is limited by potentially fatal complications that arise from alloreactive T cells also present in the lymphocyte infusion. Inflammatory reactions to T cell therapy can also cause severe tissue damage in affected organs during a therapeutic response. One means of reducing the risk of GvHD is the use of antigen specific cytotoxic T lymphocytes rather than unmanipulated cells. This strategy was initially evaluated by investigators in Seattle, when cytomegalovirus (CMV)-specific CD8 T cell clones were administered to recipients of matched sibling grafts. There were no adverse effects from the adoptive transfer of these clones. Furthermore CMV specific immune responses were reconstituted and no patients developed CMV disease. Post-transplant EBV-LPD is an excellent model in which to evaluate the efficacy of adoptively transferred antigen-specific CTL. The tumor cells express all latent-cycle virus-encoded antigens (EBNAs 1,2,3A, 3B, 3C, LMP1, 2a and 2b), most of which are targets for virus-specific immune responses, as well as several co-stimulatory molecules that facilitate CTL generation. EBV-transformed B lymphoblastoid cell lines (LCL) that can readily be prepared from any donor provided a source not only of antigen-presenting cell that endogenously expresses the appropriate viral antigens, but also of autologous target cells bearing the tumor antigens for CTL testing. Furthermore, most donors are immune to EBV and carry a high frequency of EBV-specific CTL precursors.

该子项目是利用资源的众多研究子项目之一由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持并且子项目的主要研究者可能是由其他来源提供的，包括其他 NIH 来源。子项目可能列出的总成本代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 EB 病毒 (EBV) 是一种潜伏性疱疹病毒，可感染 90% 以上的人口。原发感染通常会导致轻微的自限性疾病，随后病毒在口腔上皮细胞和 B 细胞中终身潜伏。在 T 细胞免疫受损的宿主中，EB 病毒的重新激活可导致不受控制的淋巴增殖，进而演变成免疫母细胞淋巴瘤。在来自 HLA 匹配的无关供体或不匹配的相关供体的同种异体骨髓的受者中，供体和受者之间的遗传差异导致移植物抗宿主病 (GvHD) 的高风险。体外去除供体骨髓的 T 细胞可有效降低这种风险，但也会延迟免疫恢复并增加病毒感染的发生率，包括由 EBV 转化的 B 细胞生长引起的 Epstein-Barr 病毒淋巴增殖性疾病 (EBV-LPD)。移植后发生 EBV-LPD 的危险因素包括使用不匹配的相关或密切匹配的非相关供体的骨髓、供体骨髓的 T 细胞耗竭以及强化免疫抑制。在具有这些易感特征且对化疗或α干扰素反应不佳的患者中，EBV-LPD 的发生率为 5% 至 25%。来自供体外周血的未经选择的淋巴细胞群通常含有 EBV 特异性 T 细胞，因此可用于控制 EBV 淋巴增殖性疾病。然而，这种疗法的使用受到淋巴细胞输注中也存在的同种异体反应性 T 细胞引起的潜在致命并发症的限制。 T 细胞治疗的炎症反应也会在治疗反应期间导致受影响器官的严重组织损伤。降低 GvHD 风险的一种方法是使用抗原特异性细胞毒性 T 淋巴细胞而不是未经操作的细胞。这一策略最初由西雅图的研究人员进行了评估，当时将巨细胞病毒 (CMV) 特异性 CD8 T 细胞克隆施用于匹配的同胞移植物的受者。这些克隆的过继转移没有产生任何不利影响。此外，CMV 特异性免疫反应得到重建，没有患者出现 CMV 疾病。移植后 EBV-LPD 是评估过继转移抗原特异性 CTL 功效的绝佳模型。肿瘤细胞表达所有潜伏周期病毒编码的抗原（EBNA 1,2,3A, 3B, 3C, LMP1, 2a 和 2b），其中大部分是病毒特异性免疫反应的目标，以及一些共刺激促进CTL生成的分子。 EBV 转化的 B 类淋巴母细胞系 (LCL) 可以很容易地从任何供体中制备，不仅提供了内源表达适当病毒抗原的抗原呈递细胞的来源，而且还提供了带有用于 CTL 测试的肿瘤抗原的自体靶细胞的来源。此外，大多数供体对 EBV 具有免疫力，并且携带高频率的 EBV 特异性 CTL 前体。