Immunotherapy for EBV Positive Hodgkin's Disease

描述（由申请人提供）：化疗难治性患者 霍奇金病（HD）的治疗选择很少。大约40%的 所有HD病例都显示与爱泼斯坦巴尔病毒（EBV）有关， 其特征在于感染的II型潜伏模式和表达较少的 潜伏期III肿瘤中的EBV抗原。先前的研究已经证实， EB病毒诱导干细胞淋巴细胞增殖的过继免疫治疗 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）可导致疾病缓解。它 类似的策略对于延迟类型II是可能成功的 紊乱本研究的目的是检查临床和 输注HLA来源EB病毒特异性CTL免疫效应 复发性/难治性， EB病毒阳性HD。CTL识别的EBV抗原谱 还将确定来自制备和输注后患者T细胞的 作为EBV特异性CTL前体（CTLp）水平，通过有限稀释分析 （LDA）。治疗结果将通过临床和影像学评估 终点，并将与供体/宿主HLA差异的水平相关， 针对潜伏期II抗原的CTL反应性和EBV CTLp水平 输注后。我们将使用短串联的PCR测定来追踪输注的CTL。 重复序列（STR）。虽然最初的一组患者将接受EBV CTL， 既往免疫抑制，随后的患者队列将接受单次免疫抑制， 氟达拉滨后的CTL输注，其将用作免疫抑制剂。 促进淋巴移植的试剂。由于免疫抑制可能会增加 移植物抗宿主病的风险、CTL输注液和患者血液 将检查标本中是否存在供体来源的、受体来源的 特异性T细胞为了评估CTL排斥反应的风险，LDA也将被 对输注后血液标本进行检测，以检测宿主来源的CD 4和CD 8 对供体抗原具有反应性的细胞。本研究将提供 关于1）用同种异体EBV特异性CTL治疗是否具有临床意义的信息 对EBV阳性HD的疗效; 2）如果有效，这是否与 与特异于EBV潜伏期II型抗原的效应细胞，和3）如果不是， 有效，失败是否与短半衰期有关 输注CTL。

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.