Enhancing the Safety of Allogeneic Transplantation

描述（由申请人提供）：多中心协作以降低异基因造血细胞移植（HCT）的固有风险对于降低方案毒性、感染、输血依赖、移植物抗宿主病（GVHD）和恶性复发的危险至关重要。解决所有这些风险的持续努力一直是明尼苏达大学研究人员参与网络的重点。我们对该网络的承诺包括作为指导委员会主席、四项协议的国家PI参与，领导前四项网络出版物，并投入机构资源开发和成功执行网络试验。由于脐带血（UCB）移植仍然受到移植延迟或失败的限制，我们启动了研究，以增加UCB移植物的归巢和造血恢复的基础上，临床前数据表明，补体片段C3a可以实现这些目标。正在进行的明尼苏达大学I期试验测试了一对UCB单元之一的C3a预充，以增加植入并增强预充单元的优势，为拟定的多中心11期试验提供了临床背景。我们提出了一个协议测试是否C3a引发的一个UCB单位可以增加该单位的优势作为移植造血源的可能性，可以增强和加速多系造血恢复，并可以增强免疫重建，从而减少感染的风险，没有多余的移植物抗宿主病。我们继续致力于网络在开发新方案、确定适合网络试验入组的患者和执行方案特定程序方面的成功。我们将努力超越网络的标准，致力于提高多中心试验的成功率，并推动网络内的科学进步。多中心协作试验对于正式测试提高同种异体移植安全性和改善患者结局的新方法至关重要。 公众相关性：改善过敏性移植的结果需要控制早期毒性、感染风险、输血依赖、移植物抗宿主病和复发。BMT CTN内的多中心试验已经解决了所有这些领域，在明尼苏达大学，我们致力于推进高质量网络试验的开发和执行。我们建议通过用补体片段C3a启动一对UCB单位之一来增加脐带血植入的成功率，以将明尼苏达大学的初步数据扩展到多中心II期试验。改善移植物植入和移植后免疫恢复可能会限制这些危害，并增加所有移植的成功率。

DESCRIPTION (provided by applicant): Multicenter collaboration to reduce the risks inherent in allogeneic hematopoietic cell transplantation (HCT) is essential to dampen the dangers of regimen toxicity, infection, transfusion dependence, graft vs. host disease (GVHD) and malignant relapse. Ongoing efforts to address all these risks have been a focus of Network participation for investigators at the University of Minnesota. Our commitment to the Network has included participation as Steering Committee chair, national PI of four protocols, leading the first four Network publications and committing institutional resources to develop and successfully execute Network trials. Because umbilical cord blood (UCB) transplantation is still limited by delayed or failed engraftment, we initiated studies to augment the homing and hematopoietic recovery of UCB grafts based on preclinical data suggesting that complement fragment C3a can accomplish these goals. An ongoing University of Minnesota phase 1 trial testing C3a priming of one of a pair of UCB units to augment engraftment and enhance predominance of the primed unit provides the clinical background for a proposed multicenter phase 11. We propose a protocol testing whether C3a priming of one UCB unit can increase the likelihood of that unit's predominance as the engrafting hematopoietic source; can augment and accelerate multilineage hematopoietic recovery; and can enhance immune reconstitution thereby lessening risks of infection without excess graft vs. host disease. We offer our continued commitment to the Network's success in developing new protocols, identifying patients suitable for Network trial enrollment and performing protocol specific procedures. We will try to exceed the Network's standards in our commitment to enhance multicenter trial success and advance scientific progress within the Network. Multicenter collaborative trials are essential to formally test new ways to enhance the safety of allotransplantation and improve outcomes for our patients. PUBLIC RELEVANCE: Improvement in the outcomes of allergenic transplantation requires control of early toxicity, risks of infection, transfusion dependence, graft vs. host disease and relapse. Multicenter trials within the BMT CTN have tackled all these areas and at the University of Minnesota we are committed to advancing the development and execution of high-quality Network trials. We propose augmenting the success of umbilical cord blood engraftment by priming one of a pair of UCB units with complement fragment C3a, to extend preliminary University of Minnesota data to a multicenter phase II trial. Improving engraftment and post transplant immune recovery may limit these hazards and augment the success of all transplantation.