STROMAL EFFECTS ON UMBILICAL CORD BLOOD EXPANSION

来自脐带血（UCB）的同种异体造血干细胞和祖细胞（HSC）移植已被用来治疗缺乏传统骨髓（BM）供体的患者。在无关 UCB 移植的成人和儿童受者中，预测成功结果（无事件生存期，EFS）的主要因素是移植的细胞剂量。先前的工作表明，UCB HSC 可以在封闭的自动化 AastromReplicell™ 细胞生产系统 (ARS) 中进行适度的离体扩增。 I 期小规模研究表明，在 UGB 培养物中添加骨髓来源的基质细胞可显着增加 HSC 的生成数量。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，包括在基质存在的情况下 NOD/scid 再生细胞。优化后的 UGB：基质培养物的放大将在 ARS 中得到验证，并建议进行临床试验来测试扩大的 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，使用改良的增强方案或替代策略，在干细胞移植中使用最佳扩展的 UCB。成功开发和实施改进的扩展过程将导致 UCB 移植的更大临床效用。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 移植中限制细胞剂量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 UCB 扩增过程可能会增加 AastromReplicell(TM) 细胞生产系统的临床应用，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.