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）后发生的中性粒细胞恢复的显著延迟，我们成功开发了一种新的临床可行的方法，该方法利用工程化Notch配体离体产生增加数量的CD 34+祖细胞。我们以前已经证明，在接受清髓性部分HLA匹配CBT的患者中，将扩增细胞沿着输注常规未操作单位可以显著减少中性粒细胞恢复的时间。现在，为了开发一种更经济和临床可行的扩增造血祖细胞来源，我们专注于评估我们的扩增祖细胞产品作为一种“现成的治疗方法，而无需HLA匹配。我们已经建立了一个小的CB祖细胞“银行”，已经离体扩增和冷冻保存以备将来使用，并且正在进行试点临床试验以评估这种方法的安全性。 四名患者已经入组并接受了标准CBT，输注了来自我们银行的非HLA匹配的扩展产品。输注本品在所有患者中均耐受良好，未观察到毒性或GVHD增加的证据。此外，对CBT后供体嵌合体的分析已经证实了扩增细胞提供快速低水平骨髓植入爆发的能力，具有可能的促进活性，其可以增强从未操作的细胞的重建。我们现在准备进行一项II期随机、多中心的前瞻性研究，在血液恶性肿瘤患者中使用或不使用离体扩增的现成CB祖细胞进行CBT。主要目的是比较两组的植活时间。次要目的旨在进一步评估临床和经济学（例如，至血小板恢复的时间、首次住院的持续时间、第200天TRM和重度感染的发生率）。在实验室进行的研究旨在更好地了解预测植入动力学、体内持久性和我们现成产品的促进活性的因素， 重点是HLA的作用和输注产品的细胞组成。相关性：脐带血移植与早期移植相关死亡的风险增加有关，这是由于移植后长时间的严重中性粒细胞减少。我们已经开发了新的方法，用于脐带血祖细胞的体外扩增，能够在输注后提供早期中性粒细胞植入的快速爆发。我们的目标是在II期临床试验中确定这种方法的临床疗效。

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.