CYTOTOXIC T CELL TRANSFER FOR THERAPY OF EBV LYMPHOMA

描述(改编自申请人摘要)：腺病毒， 巨细胞病毒(CMV)和EB病毒(EBV)是最常见的三种 同种异体免疫低下患者致死性病毒性疾病的原因 干细胞移植(SCT)。目前尚无治疗腺病毒的药物 或EBV感染，而传统的CMV试剂有许多局限性。 因此，基于T细胞的疗法的使用引起了相当大的兴趣 恢复对这些病原体的免疫力。当前的应用程序构建在此基础上 该小组早期的工作表明，EBV特异性CTL是由 供体T细胞与供体EBV转化的淋巴母细胞系(LCL)可以 安全地给予SCT接受者，并作为有效的EBV 预防措施。此外，输液前CTL的基因标记显示 这些细胞长期存在，并渗透和破坏部位。 活动性EB病毒淋巴瘤。这项拨款现在提议使用极好的抗原 EBV-LCL呈递特性以呈递额外抗原，来源 从腺病毒和CMV，最终从单个 对所有三种病毒都有特异性的培养。三个具体目标 是基于大量的临床前可行性数据。在目标1中，患者 将继续接受EBV特异性CTL，但将获得额外的基因 在剂量递增研究中标记的腺病毒特异性CTL，以建立 他们的安全和坚持不懈。在目标2中，EBV-LCL本身将被脉冲 并用于产生识别两种EBV的双特异性株系 和CMV。这些将被注入患者体内，他们的坚持不懈和 测定了抗病毒免疫活性。在AIM 3中，EBV-LCL将被脉冲 腺病毒和CMV，并制备了三特异性CTL细胞系。跟随 输液后，其安全性、持久性和抗病毒免疫活性将 下定决心。这项计划是为了开发一种基于细胞的抗病毒疗法 源自单一的文化体系，将提供一种实用和 预防SCT后这三种致命感染的经济有效的手段。

DESCRIPTION (Adapted from Applicant's Abstract): Adenovirus, cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are the three commonest causes of lethal viral disease in patients immunocompromised by allogeneic stem cell transplantation (SCT). No drugs are available to treat adenovirus or EBV infections, and conventional agents for CMV have many limitations. Hence there is considerable interest in the use of T-cell based therapies to restore immunity to these pathogens. The current application builds on this group's earlier work, showing that EBV specific CTL generated by culture of donor T cells with donor EBV-transformed lymphoblastoid cell lines (LCL) can be safely administered to SCT recipients and act as effective EBV prophylaxis. Moreover, gene marking the CTL before infusion showed that these cells persisted long term and infiltrated and destroyed sites of active EBV lymphoma. This grant now proposes to use the excellent antigen presenting properties of EBV-LCL to present additional antigens, derived from adenovirus and CMV, ultimately generating a CTL line from a single culture that has specificity for all three viruses. The three Specific Aims are based on substantial pre-clinical feasibility data. In Aim 1, patients will continue to receive EBV-specific CTL but will receive in addition gene marked adenovirus specific CTL in a dose escalation study, to establish their safety and persistence. In Aim 2, EBV-LCL themselves will be pulsed with adenovirus and used to generate bi-specific lines recognizing both EBV and CMV. These will be infused into patients and their persistence and anti-viral immune activity measured. In Aim 3, EBV-LCL will be pulsed with both adenovirus and CMV, and tri-specific CTL lines prepared. Following infusion, their safety, persistence and anti-viral immune activity will be determined. This plan to develop a cell based anti-viral therapeutic that derives from a single culture system, will offer a practical and cost-effective means of preventing these three lethal infections after SCT.