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，我们成功地开发了一种新的、临床上可行的方法，利用工程Notch配体在体外产生更多数量的CD34+祖细胞。我们之前已经证明，在接受部分与人类白细胞抗原相合的骨髓清除性CBT的患者中，将扩增的细胞与传统的非操作单元一起输注可以显著缩短中性粒细胞恢复的时间。现在，为了努力开发一种更经济和临床上可行的扩增造血祖细胞来源，我们专注于评估我们的扩增造血祖细胞产品是一种不需要HLA配型的现成疗法。我们已经建立了一小部分体外扩增和冷冻保存的脐带血前体细胞以供将来使用，目前正在进行一项试点临床试验，以评估这种方法的安全性。有4名患者入选接受了标准的CBT，输注了我们银行生产的非相合扩展产品。该产品在所有患者中的耐受性良好，没有观察到毒性或GVHD增加的证据。此外，对CBT后供体嵌合体的分析证实，扩增的细胞能够提供快速、低水平的髓系植入，可能具有促进作用的激活，可以促进未被操纵的细胞的重建。我们现在准备进行一项第二阶段的随机多中心前瞻性研究，研究恶性血液病患者使用或不使用体外扩增的脐带血祖细胞的CBT。主要目标将是比较两组植入的时间。次要目标旨在进一步评估临床和经济(例如，血小板恢复时间、首次住院时间、第200天TRM和严重感染发生率)也将收集。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， 重点放在人类白细胞抗原的作用和输注产品的细胞组成上。相关性：脐带血移植与早期移植相关死亡的风险增加有关，因为移植后严重的中性粒细胞减少症持续时间较长。我们已经开发了脐血祖细胞体外扩增的新方法，能够在输注后提供早期中性粒细胞植入的快速爆发。我们的目标是现在在II期临床试验中确定该方法的临床疗效。

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.