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后发生的嗜中性粒细胞恢复的显着延迟（CBT），我们成功地开发了一种新型且临床上可行的方法论，该方法利用了工程化的Notch配体，用于体内增加CD34+祖细胞数量增加。我们以前已经证明，在接受髓裂部分HLA匹配的CBT的患者中，膨胀细胞的输注以及常规的无操纵单位可以显着减少嗜中性粒细胞恢复的时间。 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这种方法已被纳入标准的CBT，并在我们的银行中添加了非HLA匹配的产品，在所有患者中都可以耐受性。这可以增强无操纵细胞的重建。主要目标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，还将收集临床和经济的恢复时间，初始住院时间，第200天的TRM和严重感染的发生率）。在实验室中进行的研究将旨在更好地了解预测植入动力学的因素，体内持久性和我们现成的产品的促进活动，即 重点是HLA的作用和产品注入的细胞组成。相关性：脐带血移植与由于长时间在移植后发生严重的中性粒细胞减少症而导致早期移植相关死亡率的风险增加。我们开发了新的方法，用于在输注后能够快速提供早期嗜中性粒细胞植入的脐带血祖细胞的体内扩张。我们的目标是现在确定II期临床试验中这种方法的临床功效。