Immunotherapy for EBV Positive Hodgkin's Disease

描述(申请人提供)：化疗难治患者 霍奇金氏病(HD)的治疗选择很少。约40%的 所有HD病例都被证明与EB病毒(EBV)有关， 以II型潜伏感染模式和较少的表达为特征 EBV抗原在潜伏期III肿瘤中的比例较低。此前的研究已经证实， EB病毒诱导干细胞淋巴组织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 类似的策略有可能对延迟类型II成功 精神错乱。这项研究的目的是检查临床和 输注供者来源的EBV特异性人类白细胞抗原特异性CTL的免疫效应 为复发/难治患者提供完全相同或半相合的供体， EB病毒阳性HD。CTL识别的EBV抗原谱 还将确定输液后的准备和患者的T细胞 极限稀释法检测EB病毒特异性CTL前体(CTLp)的AS水平 (LDA)。治疗结果将通过临床和X线片进行评估。 并将与供者/宿主的人类白细胞抗原差异水平相关， 针对潜伏期II抗原的CTL反应性和EBV CTLp水平 输液后。我们将使用短串联的聚合酶链式反应分析来追踪注入的CTL 重复(STR)。虽然最初的一组患者将接受EBV CTL，但没有 在免疫抑制之前，随后的队列患者将接受单一的 氟达拉滨后的CTL输注将用作免疫抑制 促进淋巴植入的试剂。因为免疫抑制可能会增加 移植物与宿主疾病、CTL输注和患者血液的风险 将对样本进行检查，以确定是否存在供体来源的受者 LDA法检测特异性T细胞。为了评估CTL拒绝的风险，LDA也将 对输液后的血液样本进行检测，以检测宿主来源的CD4和CD8 对供体抗原有反应性的细胞。这项研究将提供 关于1)异基因EBV特异性CTL治疗是否具有临床疗效的信息 对EBV阳性HD的疗效；2)如果有效，这是否相关 与EBV潜伏期II型抗原特异的效应细胞，以及3)如果不是 是否有效，则故障是否与 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.