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

• 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
• 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

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.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 爱泼斯坦-巴尔病毒(EBV)是一种潜伏的疱疹病毒，感染90%以上的人口。原发感染通常导致一种轻微的自限性疾病，随后口腔上皮细胞和B细胞中的病毒潜伏终生。在T细胞免疫受损的宿主中，EBV的重新激活可导致不受控制的淋巴增殖，演变为免疫母细胞淋巴瘤。供者和受者之间的遗传差异导致移植物抗宿主病(GvHD)的风险很高。在体外，供者骨髓中T细胞的耗尽有效地降低了这种风险，但也延缓了免疫恢复，并增加了病毒感染的发生率，包括EB病毒转化的B细胞的生长引起的EB病毒淋巴增殖性疾病(EBV-LPD)。EBV-LPD移植后发展的危险因素是使用不匹配的亲属或非常匹配的非亲属供者的骨髓，供者骨髓的T细胞耗尽和严重的免疫抑制。在有这些易感特征的患者中，EBV-LPD的发生率从5%到25%不等，对化疗或α干扰素的反应很差。 来自供者外周血的未经选择的淋巴细胞群体通常含有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潜在的致命并发症的限制，这些并发症来自于淋巴细胞输注中也存在的同种异体反应性T细胞。在治疗反应中，T细胞治疗的炎症反应也会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，而不是未经处理的细胞。这一策略最初是由西雅图的研究人员评估的，当时巨细胞病毒(CMV)特异性CD8T细胞克隆被注射到匹配同胞移植物的接受者身上。这些克隆的收养转移没有任何不良影响。此外，重组了CMV特异性免疫应答，无一例患者发生CMV病。移植后EBV-LPD是评估过继转移抗原特异性CTL疗效的一个很好的模型。肿瘤细胞表达所有潜伏期病毒编码的抗原(EBNAs 1，2，3a，3b，3C，LMP1，2a和2b)，其中大多数是病毒特异性免疫反应的靶标，以及几个促进CTL产生的共刺激分子。EBV转化的B淋巴母细胞系(LCL)不仅提供了内源性表达适当病毒抗原的抗原提呈细胞，而且提供了携带肿瘤抗原的自体靶细胞用于CTL检测，这种B淋巴母细胞系可以很容易地从任何供体制备。此外，大多数捐赠者对EBV免疫，并携带高频率的EBV特异性CTL前体。