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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 爱泼斯坦 - 巴尔病毒（EBV）是一种潜在的疱疹病毒，可感染超过90％的人群。 原发性感染通常会导致温和的自限性疾病，随后是口腔上皮细胞和B细胞中终生的病毒潜伏期。 在T细胞免疫力受损的宿主中，EBV的重新激活可能导致不受组织的淋巴增生发展为免疫细胞淋巴瘤。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接受者中，供体和受体之间的遗传差异会导致移植物与宿主疾病（GVHD）的高风险。供体骨髓的体外T细胞耗竭有效地降低了这种风险，但也会延迟免疫恢复并增加病毒感染的发生率，包括EBV转化B细胞的生长，包括爱泼斯坦 - 巴尔病毒淋巴增生性疾病（EBV-LPD）。 EBV-LPD移植后发展后的危险因素是使用不匹配的相关或密切匹配的无关供体的骨髓，供体骨髓的T细胞耗竭和强化免疫抑制。具有这些诱发特征的患者的EBV-LPD发病率从5％到25％，对化学疗法或α干扰素的反应较差。 供体外周血的未选择的淋巴细胞种群通常含有EBV特异性T细胞，因此可用于控制EBV淋巴增生性疾病。但是，这种疗法的使用受到淋巴细胞输注中同种反应性T细胞的潜在致命并发症的限制。在治疗反应期间，对T细胞疗法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操纵的细胞。当西雅图的研究人员评估了这种策略，当时巨细胞病毒（CMV）特异性CD8 T细胞克隆被对匹配的同胞移植物的受体进行管理。这些克隆的收养转移没有不利影响。此外，CMV特异性免疫反应进行了重构，并且没有患者患有CMV疾病。移植后EBV-LPD是一个出色的模型，可以评估采用转移的抗原特异性CTL的功效。肿瘤细胞表达所有潜在周期病毒编码的抗原（EBNAS 1,2,3a，3b，3c，3c，LMP1，2A和2B），其中大多数是病毒特异性免疫反应的靶标，以及几种共刺激性的靶标促进CTL产生的分子。 EBV转换的B淋巴细胞细胞系（LCL），可以从任何供体中易于制备，这些供体不仅可以提供抗原呈现的细胞的来源，该细胞不仅是内源表达适当的病毒抗原的抗原抗原细胞，而且还提供了具有CTL测试的肿瘤抗原的自体靶细胞。此外，大多数捐赠者对EBV免疫，并具有高频EBV特异性CTL前体。