TREATMENT OF EBV ASSOCIATED LYMPHOPROLIFERATIVE DISEASE

EBV 相关淋巴细胞增殖性疾病的治疗

• 批准号: 6522647
• 负责人: Denis James Moss
• 金额: $ 20万
• 依托单位: QUEENSLAND INSTITUTE OF MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6522647
• 关键词: Epstein Barr virus; artificial immunosuppression; blood disorder; clinical trial phase I; cytotoxic T lymphocyte; enzyme linked immunosorbent assay; genetic markers; heart transplantation; human subject; human therapy evaluation; immunotherapy; lung transplantation; passive immunization; patient oriented research; virus DNA

The treatment of Epstein-Barr virus (EBV)-associated lymphoproliferative disease in solid organ transplant patients poses a considerable challenge due to the underlying immunosuppression which inhibits the virus-specific cytotoxic T cell (CTL) response in vivo. Preliminary studies developed in our laboratory suggest that it may be possible to overcome this inherent problem using a novel protocol to activate autologous EBV-specific CTL lines from these patients and to show for the first time their potential use for immunotherapy against PTLD in solid organ transplant patients. To establish the clinical use of this protocol, we propose to conduct a phase I/II clinical trial in a cohort of solid organ transplant patients with PTLD. To achieve this, we have drawn together scientific expertise within the EBV Unit at QIMR and major transplant units in Australia. In the first instances, we propose to further refine the in vitro conditions for activating EBV-specific CTL from solid organ transplant patients who are on high levels of immunosuppression. Two absolute requirements have been set: (1) EBV specificity at the CTL peptide epitope level; and (2) complete lack of anti-donor alloreactivity which would threaten the integrity of the transplanted graft. Having defined these conditions, we propose to conduct a phase I/II trial by adoptively transferring autologous EBV-specific CTL into solid organ heart, lung, and heart/lung transplant patients with PTLD. As far as we are aware, this represents the first such trial to be conducted and seeks to (1) determine the safety of adoptively transferring EBV-specific CTL into solid organ transplant patients; (2) determine the longevity of these CTL in vivo using a genetic marker; and (3) determine the extent of clinical regression of PTLD.

实体器官移植患者的 Epstein-Barr 病毒 (EBV) 相关淋巴增殖性疾病的治疗提出了 由于潜在的免疫抑制抑制了 体内病毒特异性细胞毒性 T 细胞 (CTL) 反应。初步研究 我们实验室开发的结果表明，有可能克服这个问题 使用新方案激活自体 EBV 特异性 CTL 的固有问题 来自这些患者的线条并首次展示它们的潜在用途 用于实体器官移植患者的 PTLD 免疫治疗。建立 该方案的临床应用，我们建议进行I/II期临床 在一组患有 PTLD 的实体器官移植患者中进行的试验。达到 为此，我们汇集了 QIMR EBV 部门的科学专业知识 和澳大利亚的主要移植单位。在第一种情况下，我们建议 进一步完善激活 EBV 特异性 CTL 的体外条件 处于高水平免疫抑制状态的实体器官移植患者。 设定了两个绝对要求：（1）CTL 肽的 EBV 特异性 表位水平； (2) 完全缺乏抗供体同种异体反应性，这将 威胁移植物的完整性。定义了这些 有条件的话，我们建议通过过继转移的方式进行I/II期试验 自体 EBV 特异性 CTL 进入实体器官心脏、肺和心/肺 患有 PTLD 的移植患者。据我们所知，这代表 首次进行此类试验，旨在 (1) 确定 将EBV特异性CTL过继转移至实体器官移植患者体内； (2)使用遗传标记确定这些CTL在体内的寿命；和 (3)确定PTLD临床消退的程度。