Notch-Mediated Expansion of Cord Blood Progenitors for Stem Cell Transplant

描述（由申请人提供）：为了克服脐带血移植（CBT）后中性粒细胞恢复的显著延迟，我们已经成功开发了一种新的临床可行的方法，利用工程Notch配体来体外生成增加数量的CD34+祖细胞。我们之前已经证明，在接受骨髓清除部分hla匹配CBT的患者中，输注扩增细胞与传统的未操作单元可以显着缩短中性粒细胞恢复的时间。现在，在努力开发一种更经济和临床可行的扩增造血祖细胞来源的过程中，我们专注于评估我们的扩增祖细胞产品作为一种“不需要hla匹配的现成治疗”。我们已经建立了一个小型的CB祖细胞“库”，这些祖细胞已经体外扩增并冷冻保存以备将来使用，并且正在进行一项临床试验来评估这种方法的安全性。四名患者已入组并接受了标准CBT，并注入了我们银行的非hla匹配扩展产品。本品输注在所有患者中耐受性良好，没有观察到毒性或GVHD增加的证据。此外，对CBT后供体嵌合的分析证实了扩增细胞提供快速低水平骨髓植入的能力，可能具有促进活性，可以增强未经处理的细胞的重建。我们现在准备开展一项II期随机、多中心前瞻性研究，在血液恶性肿瘤患者中使用或不使用体外扩增的现成CB祖细胞进行CBT治疗。主要目的是比较两组移植的时间。次要目标是进一步评估临床和经济（如血小板恢复时间、初次住院时间、第200天TRM和严重感染发生率）。在实验室进行的研究将旨在更好地了解预测我们现成产品的植入动力学、体内持久性和促进活性的因素。

DESCRIPTION (provided by applicant): With the goal of overcoming the significant delay in neutrophil recovery that occurs following cord blood transplantation (CBT), we have successfully developed a novel and clinically feasible methodology utilizing an engineered Notch ligand for the ex vivo generation of increased numbers of CD34+ progenitor cells. We have previously demonstrated that, in patients undergoing a myeloablative partially HLA-matched CBT, infusion of the expanded cells along with a conventional unmanipulated unit can significantly reduce the time to neutrophil recovery. Now, in an effort to develop a more economically and clinically feasible source of expanded hematopoietic progenitor cells, we are focused on evaluating our expanded progenitor cell product as an "off-the-shelf therapy without the need for HLA-matching. We have established a small "bank" of CB progenitors that have been ex vivo expanded and cryopreserved for future use, and a pilot clinical trial is underway to evaluate the safety of this approach. Four patients have been enrolled and undergone a standard CBT with infusion of a non HLA-matched expanded product from our bank. Infusion of this product has been well-tolerated in all patients, without observed toxicities or evidence for increased GVHD. Furthermore, analysis of donor chimerism post CBT has confirmed the ability of the expanded cells to provide a rapid low level burst of myeloid engraftment, with possible facilitation activit that can enhance reconstitution from the unmanipulated cells. We are now poised to conduct a Phase II randomized, multi-center prospective study of CBT with or without ex vivo expanded off-the-shelf CB progenitor cells in patients with hematologic malignancies. The primary objective will be to compare the time to engraftment in the two groups. Secondary objectives are aimed at further assessment of clinical and economic (e.g. time to platelet recovery, duration of initial hospitalization, day 200 TRM and incidence of severe infection) will also be collected. Studies conducted in the lab will be aimed at better understanding the factors that predict engraftment kinetics, in vivo persistence and facilitation activity from our off-the-shelf product, with a focus on the role of HLA and the cellular composition of the product infused. RELEVANCE: Cord blood transplantation is associated with increased risk of early transplant related mortality due to a prolonged period of severe neutropenia post transplant. We have developed novel methods for the ex vivo expansion of cord blood progenitors capable of providing a rapid burst of early neutrophil engraftment after infusion. Our goal is to now determine the clinical efficacy of this approach in a phase II clinical trial.