STROMAL EFFECTS ON UMBILICAL CORD BLOOD EXPANSION

脐带血(UCB)异基因造血干/祖细胞(HSC)移植已被用于治疗缺乏传统骨髓供者的患者。无论是成人还是儿童，预测成功结果(无事件存活，EFS)的主要因素是细胞剂量移植。以前的工作表明，UCB HSC可以在封闭的自动化AstromReplicell(TM)细胞生产系统(ARS)中适度体外扩展。第一阶段的小规模研究表明，在UGB培养中加入骨髓来源的基质细胞显著增加了HSC的生成数量。在第二阶段的研究中，将检验培养变量(接种密度、培养基灌注量、细胞因子)的影响，以进一步优化HSC的生产，包括在基质存在的情况下NOD/SCID重新繁殖细胞。优化的UGB的放大：基质培养将在ARS中得到验证，并提议进行临床试验，以测试扩大的HSG的安全性和有效性，以增强标准的脐带血移植。第三阶段研究将继续在干细胞移植中使用最佳扩大的脐带血进行临床试验，使用改进的增强方案或替代策略。成功开发和实施改进的扩张过程将使脐带血移植在临床上发挥更大的作用。拟议的商业应用：一种封闭的、自动化的、GMP系统用于脐带血细胞的体外扩增，作为克服脐带血移植中细胞剂量限制的手段，具有重要的临床和商业价值。通过使用骨髓基质层改进脐带血扩展过程可能会导致AstromReplicell(TM)细胞生产系统的更多临床应用，以及产生新的方案和试剂盒来实施改进的过程。

Transplantation of allogeneic hematopoietic stem and progenitor cells (HSC) from umbilical cord blood (UCB) has been utilized to treat patients lacking traditional bone marrow (BM) donors. In both adult and pediatric recipients of unrelated UCB grafts, the major factor predicting successful outcomes (event-free survival, EFS) is cell dose transplanted. Previous work has shown that UCB HSC can be modestly expanded ex vivo in the closed automated AastromReplicell(TM) Cell Production System (ARS). The Phase I small-scale studies have shown that the addition of BM-derived stromal cells to UGB cultures significantly increased the number of HSC generated. In Phase II studies, the effects of culture variables (inoculum density, medium perfusion, cytokines) will be examined to further optimize HSC production, including NOD/scid repopulating cells, in the presence of stroma. Scale-up of the optimized UGB:stromal cultures will be validated in the ARS, and clinical trials are proposed to test the safety and efficacy of expanded HSG to augment standard UCB transplants. Phase III studies will continue to pursue clinical trials using optimally expanded UCB in stem cell transplants using either modified augmentation protocols or replacement strategies. Successful development and implementation of an improved expansion process will lead to greater clinical utility of UCB transplantation. PROPOSED COMMERCIAL APPLICATIONS: A closed automated, GMP system for ex vivo UCB cell expansion is of significant clinical and commercial value as a means of overcoming limiting cell dose in UCB transplants. Improving the UCB expansion process through the use of bone marrow stromal layers may result in increased clinical application of the AastromReplicell(TM) Cell Production System, as well as the generation of new protocols and kits to implement the improved process.