Enhancing the Safety of Allogeneic Transplantation

描述（由申请人提供）：多中心合作降低同种异体造血细胞移植（HCT）固有的风险对于抑制方案毒性、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网络参与的重点。我们对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，领导前四份网络出版物，并投入机构资源开发和成功执行网络试验。由于脐带血（UCB）移植仍然受到延迟或植入失败的限制，我们启动了基于临床前数据的研究，以增强UCB移植物的归家和造血恢复，这些数据表明补体片段C3a可以实现这些目标。正在进行的明尼苏达大学一期试验测试了一对UCB单元之一的C3a引物，以增加植入并增强引物单元的优势，为拟议的多中心11期临床背景。我们提出了一个方案，测试C3a启动一个UCB单位是否可以增加该单位作为移植造血源的优势的可能性；能增强和加速多系造血恢复；并且可以增强免疫重建，从而减少感染的风险，而不会产生过多的移植物抗宿主病。我们将继续致力于网络在开发新协议、确定适合网络试验登记的患者和执行协议特定程序方面的成功。我们将努力超越该网络的标准，致力于提高多中心试验的成功率，并在该网络内推动科学进步。多中心合作试验对于正式测试增强同种异体移植安全性和改善患者预后的新方法至关重要。

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.