STROMAL EFFECTS ON UMBILICAL CORD BLOOD EXPANSION

来自脐带血（UCB）的异基因造血干细胞和祖细胞（HSC）的移植已被用于治疗缺乏传统骨髓（BM）供体的患者。在无关脐血移植的成人和儿童受者中，预测成功结局（无事件生存期，EFS）的主要因素是移植的细胞剂量。先前的工作已经表明，UCB HSC可以在封闭的自动化AastromReplicell（TM）细胞生产系统（ARS）中适度地离体扩增。I期小规模研究表明，向UGB培养物中添加BM来源的基质细胞显著增加了生成的HSC的数量。在II期研究中，将检查培养变量（接种密度、培养基灌注、细胞因子）的影响，以进一步优化HSC生产，包括在基质存在下的NOD/scid再增殖细胞。优化UGB的规模扩大：将在ARS中验证基质培养物，并建议进行临床试验以测试扩大HSG以增强标准UCB移植的安全性和有效性。III期研究将继续进行临床试验，在干细胞移植中使用最佳扩增的UCB，使用改良的扩增方案或替代策略。成功开发和实施一个改进的扩增过程将导致更大的脐带血移植的临床效用。拟议的商业应用：用于离体UCB细胞扩增的封闭式自动化GMP系统作为克服UCB移植中有限细胞剂量的手段具有显著的临床和商业价值。通过使用骨髓基质层改进UCB扩增过程可能导致AastromReplicellTM细胞生产系统的临床应用增加，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.