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

Notch介导的脐带血祖细胞扩增用于干细胞移植

• 批准号: 8211894
• 负责人: Colleen Delaney
• 金额: $ 267.06万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-16 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8211894
• 关键词: Award; Blood Platelets; Blood donor; CD34 gene; Cells; Chimerism; Clinical; Clinical Trials; Clinical assessments; Country; Cryopreserved Cell; Cyclic GMP; DNA; Data; Development; Dose; Economics; Engineering; Engraftment; Enrollment; Ensure; Equipment and supply inventories; Ethnic Origin; Future; Generations; Goals; Hematologic Neoplasms; Hematopoietic; Hematopoietic stem cells; Hospitalization; Human Resources; Immune; Incidence; Infection; Infusion procedures; Kinetics; Ligands; Maintenance; Measures; Mediating; Methodology; Methods; Myelogenous; Natural Killer Cells; Neutropenia; Outcome; Patients; Phase; Phase II Clinical Trials; Pilot Projects; Principal Investigator; Production; Prospective Studies; Randomized; Recovery; Resources; Risk; Role; Safety; Shipping; Ships; Source; Staging; Stem cell transplant; Stem cells; Testing; Time; TimeLine; Toxic effect; Transplant Recipients; Transplantation; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; Update; arm; clinical efficacy; clinical research site; clinically relevant; cost effective; efficacy trial; graft vs host disease; high risk; in vivo; method development; mortality; neutrophil; notch protein; novel; open label; peripheral blood; progenitor; reconstitution; stem; trial comparing

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.

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着延迟，我们成功开发了一种新颖且临床可行的方法，利用工程化的Notch配体在体外生成增加的中性粒细胞。 CD34+祖细胞的数量。我们之前已经证明，在接受清髓性部分 HLA 匹配 CBT 的患者中，将扩增的细胞与传统的未操作单元一起输注可以显着缩短中性粒细胞恢复的时间。现在，为了开发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祖细胞产品作为“无需 HLA 匹配的现成疗法”。我们已经建立了一个小型的 CB 祖细胞“库”已经离体扩增并冷冻保存以供将来使用，一项试点临床试验正在进行中，以评估这种方法的安全性，四名患者已入组并接受了治疗。输注我们银行的非 HLA 匹配扩增产品的标准 CBT 输注在所有患者中均具有良好的耐受性，没有观察到毒性或 GVHD 增加的证据。此外，CBT 后供体嵌合的分析也证实了这种能力。扩增的细胞以提供快速低水平的骨髓移植，并可能具有促进未操作细胞重建的活性，我们现在准备进行 II 期随机、对患有血液系统恶性肿瘤的患者进行 CBT（有或没有离体扩增现成 CB 祖细胞）的多中心前瞻性研究。主要目标是比较两组的植入时间。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、初次住院时间、200 天 TRM 和严重感染发生率）。在实验室进行的研究旨在更好地了解我们现成产品的预测植入动力学、体内持久性和促进活性的因素， 重点关注 HLA 的作用和输注产品的细胞成分。相关性：由于移植后长期出现严重中性粒细胞减少症，脐带血移植与早期移植相关死亡风险增加有关。我们开发了脐带血祖细胞离体扩增的新方法，能够在输注后快速爆发早期中性粒细胞植入。我们现在的目标是在 II 期临床试验中确定这种方法的临床疗效。