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: 8166752
• 负责人: HELEN E HESLOP
• 金额: $ 0.08万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8166752
• 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 Trials; Computer Retrieval of Information on Scientific Projects Database; 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; Institution; Interferon-alpha; LMP1; Large-Cell Immunoblastic Lymphoma; Lead; Life; Lymphocyte; Lymphoproliferative Disorders; Marrow; Modeling; Oral; Organ; Patients; Population; Reaction; Recovery; Research; 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; graft vs host disease; high risk; lymphoblastoid cell line; neoplastic cell; peripheral blood; reconstitution; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 EB病毒（EBV）是一种潜伏性疱疹病毒，感染超过90%的人口。 原发性感染通常导致轻微的自限性疾病，随后是口腔上皮细胞和B细胞中的终身病毒潜伏期。 在T细胞免疫受损的宿主中，EBV的再活化可导致不受抑制的淋巴细胞增殖，发展为免疫母细胞性淋巴瘤。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体中，供体和受体之间的遗传差异导致移植物抗宿主病（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，但也延迟了免疫恢复并增加了病毒感染的发生率，包括由EBV转化的B细胞的生长引起的EB病毒淋巴增生性疾病（EBV-LPD）。 移植后发生EBV-LPD的风险因素是使用来自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细胞耗竭和强烈的免疫抑制。EBV-LPD的发病率范围为5%至25%的患者与这些易感性的特点，并响应较差的化疗或α干扰素。 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淋巴增生性疾病。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。对T细胞治疗的炎症反应也可能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淋巴细胞而不是未操作的细胞。这种策略最初是由西雅图的研究人员评估的，当时将巨细胞病毒（CMV）特异性CD 8 T细胞克隆给予匹配的同胞移植物受体。这些克隆的过继转移没有不良反应。此外，CMV特异性免疫应答被重建，并且没有患者发展为CMV疾病。移植后EBV-LPD是评估过继转移抗原特异性CTL的有效性的极好模型。肿瘤细胞表达所有潜伏周期病毒编码的抗原（EBNAs 1、2、3A、3B、3C、LMP 1、2a和2b），其中大多数是病毒特异性免疫应答的靶标，以及促进CTL产生的几种共刺激分子。可以容易地从任何供体制备的EBV转化的B类淋巴母细胞系（LCL）不仅提供了内源性表达适当病毒抗原的抗原呈递细胞的来源，而且提供了携带用于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，并携带高频率的EBV特异性CTL前体。