Immunotherapy for EBV Positive Hodgkin's Disease

EBV 阳性霍奇金病的免疫治疗

• 批准号: 6446401
• 负责人: KENNETH G LUCAS
• 金额: $ 29.06万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6446401
• 关键词: Epstein Barr virus; Hodgkin's disease; artificial immunosuppression; combination cancer therapy; cytotoxic T lymphocyte; flow cytometry; graft versus host disease; homologous transplantation; human subject; human therapy evaluation; immunosuppressive; microorganism immunology; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; passive immunization; patient oriented research; vaccinia virus; virus related neoplasm /cancer

DESCRIPTION (Provided by applicant): Patients with chemotherapy-refractory Hodgkin's disease (HD) have few treatment options. Approximately 40 percent of all cases of HD have been shown to be associated with Epstein Barr virus (EBV), characterized by a type II Latency pattern of infection and expression of fewer EBV antigens than in Latency III tumors. Previous studies have established that adoptive immunotherapy for EBV-induced lymphoproliferations in stem cell transplant and organ transplant patients (Latency III infections) with EBV-specific cytotoxic T lymphocytes (CTL) can lead to remission of disease. It is possible that similar strategies would be successful for Latency type II disorders. The objective of this study is to examine the clinical and immunologic effects of infusing donor-derived, EBVspecific CTL from HLA identical or haplo-identical donors for patients with relapsed/refractory, EBV-positive HD. The spectrum of the EBV antigens recognized by the CTL preparation and from patient T cells post-infusion will be determined, as well as levels of EBV specific CTL precursors (CTLp) by limiting dilution analysis (LDA). The therapeutic outcome will be assessed with clinical and radiographic endpoints and will be correlated with the level of donor/host HLA disparity, CTL reactivity against Latency II antigens, and levels of EBV CTLp post-infusion. We will track the infused CTL using PCR assays for short tandem repeats (STR). While the initial group of patients will receive EBV CTL without prior immunosuppression, subsequent cohorts of patients will receive a single CTL infusion following fludarabine, which will be used as an immunosuppressive agent to facilitate lymphoid engraftment. Since immunosuppression may increase the risk of graft vs. host disease, the CTL infusates and patient blood specimens will be examined for the presence of donor-derived, recipient specific T cells by LDA. To assess risk for CTL rejection, LDA will also be performed on post-infusion blood specimens to detect host-derived CD4 and CD8 cells with reactivity against donor antigens. This study will provide information on 1) whether therapy with allogeneic EBV specific CTL has clinical efficacy against EBV-positive HD; 2) if effective, whether this is correlated with effector cells specific to EBV latency type II antigens, and 3) if not effective, whether the failure is associated with a short half-life of the infused CTL.

描述（由申请人提供）：化学治疗难治性患者 霍奇金氏病（HD）几乎没有治疗选择。大约40％ 所有HD病例均已证明与爱泼斯坦Barr病毒（EBV）， 以感染的II型潜伏期和较少的表达为特征 EBV抗原比潜伏期III肿瘤中的抗原。以前的研究已经确定 EBV诱导的干细胞中EBV诱导的淋巴增生的收养免疫疗法 移植和器官移植患者（潜伏期III感染） EBV特异性细胞毒性T淋巴细胞（CTL）可导致疾病的缓解。它 对于II型潜伏期，类似的策略可能会成功 疾病。这项研究的目的是检查临床和 来自HLA的注入供体衍生的EBVSpecific CTL的免疫学效应 复发/难治性患者的相同或单倍的供体， EBV阳性高清。 CTL识别的EBV抗原的光谱 还将确定入侵后的患者T细胞，也将确定 通过限制稀释分析，作为EBV特异性CTL前体（CTLP）的水平 （LDA）。治疗结果将通过临床和射线照相评估 终点，将与捐助者/主机HLA差异的水平相关， CTL对潜伏期II抗原的反应性和EBV CTLP的水平 输入后。我们将使用PCR分析进行短串联跟踪注入的CTL 重复（str）。虽然初始患者将获得EBV CTL 事先免疫抑制，随后的患者队列将获得一个 Fludarabine后CTL输注，将用作免疫抑制 促进淋巴机的药物。由于免疫抑制可能会增加 移植物与宿主病的风险，CTL注入和患者血液 将检查标本是否存在供体衍生的接收者 特异性T细胞通过LDA。为了评估CTL拒绝的风险，LDA也将是 在灌注后血液样本上进行，以检测宿主衍生的CD4和CD8 针对供体抗原的反应性的细胞。这项研究将提供 有关1）同种异体EBV特异性CTL的治疗是否具有临床 对EBV阳性高清的功效； 2）如果有效，是否相关 具有特定于EBV潜伏期II型抗原的效应细胞，3）如果不是） 有效，失败是否与短的半衰期有关 注入CTL。