Inducing and targeting of EBV lytic antigens in lymphoma

淋巴瘤中EBV裂解抗原的诱导和靶向。 EB病毒(EBV)阳性淋巴瘤包括移植后淋巴瘤、Burkitt淋巴瘤(BL)、艾滋病相关淋巴瘤(ARL)，以及某些形式的霍奇金、T细胞和自然杀伤(NK)细胞淋巴瘤。这些淋巴瘤是侵袭性的恶性淋巴瘤，通常对化疗产生抗药性。开发新的治疗方法显然是必要的。这项研究计划建议将EBV病毒作为一种 特定的淋巴瘤靶点。 EBV是一种具有两种不同生命周期的疱疹病毒：导致产生和释放新病毒粒子的产生和释放的产生周期和非产生的潜伏周期。大多数淋巴瘤细胞感染潜伏的EBV，只有10种病毒低水平表达。核因子-kappaB在调节潜伏和裂解复制之间的转换中起关键作用。 EB病毒。蛋白酶体抑制剂，通过抑制核因子-kB，被发现在体外重新激活潜伏感染细胞的潜伏EBV。其基本假设是，蛋白酶体抑制剂Bortezomib(Velade TM)可用于启动EBV相关恶性肿瘤中EBV裂解抗原的表达，从而启动病毒TK和其他病毒抗原的表达，从而 使肿瘤细胞容易被核苷类似物更昔洛韦和免疫系统的细胞杀死。 这种新的联合疗法将专门为EBV+淋巴瘤患者的治疗而开发。 目的1：确定蛋白酶体抑制剂Bortezomib从EBV+淋巴瘤细胞中重新激活潜伏EBV的条件，并在细胞培养和小鼠EBV+淋巴瘤-异种移植模型中使这些细胞对更昔洛韦增敏。 确定重新激活、副杀伤和免疫反应对新的治疗方法的贡献。 目的2：从资助期的第二年开始，启动一项可行性研究，测试蛋白酶体抑制剂Bortezomib与更昔洛韦联合治疗EBV*淋巴瘤患者的安全性和有效性。确定 与治疗相关的分子事件。 综上所述，拟议的临床方案代表了蛋白酶体抑制剂的一种新应用，源于对EBV生物学的理解，旨在开发一种新的、毒性较低的EBV+淋巴瘤生物治疗方案。 正如他的简历清楚地表明，申请人致力于淋巴瘤领域的翻译研究。这项为期3年的职业发展计划旨在促进所需的额外培训，并以可行性试验的形式将一项基础科学发现转化为诊所。我们预计会有一次成功的临床试验，并计划在K23授权期之后的一段时间内扩展到更大的多中心临床试验。

Inducing and targeting of EBV lytic antigens in lymphoma. Epstein-Barr Virus (EBV) positive lymphomas include lymphomas in the post-transplantation setting, Burkitt's lymphomas (BL), AIDS- related lymphomas (ARL), and some forms of Hodgkin, T-cell, and natural killer (NK) cell lymphomas. These tymphomas are aggressive malignant lymphomas and often become chemotherapy resistant. A clear need exists to develop novel therapeutic approaches. This research plan proposes to exploit the EBV virus as a specific lymphoma target. EBV is a herpesvirus with two different life cycles: the productive =tytic" cycle leading to the production and release of new virions and the non-productive "latent" cycle. Most lymphoma cells are infected with latent EBV, and only ten viral are expressed at low levels. NF-kappaB plays a critical role in regulating the switch between latency and lytic replication of EBV. Proteasome inhibitors, by inhibiting NF-kB were found to reactivate latent EBV from latently-infected cells in vitro. The underlying HYPOTHESIS is that the proteasome inhibitor Bortezomib (Velcade TM) can be used to initiate EBV lytic antigen expression in EBV-related malignancies, initiating the expression of viral TK and other viral antigens, thereby rendering the tumor cells susceptible to killing by the nucleoside analogue Gancyclovir and cells of the immune system. This novel combination therapy will be developed specifically for the treatment of patients with EBV+ lymphomas. AIM 1: Define the conditions by which proteasome inhibitor Bortezomib can reactivate latent EBV from EBV+ lymphoma cells and sensitize these cells to Gancyclovir in cell culture and a mouse EBV+ lymphoma -xenograft model. Determine the contribution of reactivation, by-standing killing and immune responses to the new therapeutic approach. AIM 2: Initiate a feasibility study beginning year 2 of the funding period, testing the safety and efficacy of the combination of proteasome inhibitor Bortezomib with Gancyclovir in patients with EBV* lymphomas. Determine the molecular events associated with the treatment. In summary, the proposed clinical protocol represents a novel application of proteasome inhibitors derived from the understanding of EBV biology, and aims to develop a novel, less toxic, biologic treatment protocol for EBV + lymphomas. As clearly demonstrated by his CV, the applicant has committed himself to a career in translational research in the field of lymphoma. This 3-year Career Development Plan aims to facilitate the required additional training and the translation of a basic science discovery to the clinic in form of a feasibility trial. We anticipate a successful clinical trial and plan the extension to a larger multi center clinical trial in the time following the K23 granting period.