CTRIP:Notch-Mediated Expansion of Cord Blood Progenitors for Cord Blood Transplan

CTRIP：Notch介导的脐带血祖细胞扩增用于脐带血移植

• 批准号: 7939787
• 负责人: Colleen Delaney
• 金额: $ 173.21万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7939787
• 关键词: Address; Award; Blood Cells; CD34 gene; Cell Count; Cell Culture Techniques; Cell Therapy; Cells; Cessation of life; Chimerism; Clinical; Clinical Trials; Clinical Trials Cooperative Group; Collaborations; Cyclic GMP; Engineering; Engraftment; Ethnic Origin; Funding; Future; Generations; Goals; Grant; Hematologic Neoplasms; Hematopoietic; Immune; Immunosuppression; Infection; Infusion procedures; Kinetics; Leukocytes; Ligands; Mediating; Methodology; Methods; Minnesota; Minority; Modeling; Mus; Myelogenous; Neutropenia; Patients; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Pilot Projects; Process; Randomized; Reagent; Recovery; Regimen; Relative (related person); Resources; Risk; Safety; Shipping; Ships; Site; Staging; Supportive care; T-Lymphocyte; Time; Transplantation; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; Universities; Work; clinical efficacy; cohort; design; expectation; experience; immunodeficient mouse model; in vivo; neutrophil; notch protein; novel; phase 2 study; preclinical evaluation; preclinical study; product development; progenitor; public health relevance; reconstitution

DESCRIPTION (provided by applicant): With the goal of overcoming the significant delay in neutrophil recovery that occurs following transplantation with umbilical cord blood (CB), 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+ cells. A Phase I clinical trial utilizing Notch-mediated expanded CB progenitors in patients undergoing a myeloablative cord blood transplant (CBT) is currently underway. Results from this trial have not only demonstrated the safety of this approach, but more importantly have for the first time demonstrated that rapid myeloid engraftment can be achieved following infusion of ex vivo expanded hematopoietic progenitors. A significant reduction in median time to an absolute neutrophil count of 500/<ml to just 16 days has been observed in patients receiving expanded cells as compared to a median time of 26 days (p=0.002) in a concurrent cohort of 20 patients undergoing identical treatment but with two non-manipulated CB units. Thus, although the number of patients treated to date is small (n=10), a significant effect on time to myeloid recovery has been clearly demonstrated, as has the safety and clinical feasibility of this approach. Further advancement of this methodology now depends on determination of clinical efficacy, which will require a randomized multi-institutional trial. Prior to initiation of such a trial, several critical issues will need to be addressed, including the ability to manufacture and safely ship cells to outside centers, establishment of an appropriate clinical trials and cell therapy manufacturing collaborative group(s) to conduct a future Phase II randomized multi-institutional trial, and determination of need for HLA-matching of the ex vivo expanded product for clinical use. It is our goal that at the end of the two year funding period, we will be prepared and completely ready to begin critical phase II studies. Specifically, we now propose the following aims: 1) Determine methods for shipping expanded cells to outside centers for infusion, including preclinical evaluation of in vivo repopulating ability in our established murine model of the proposed methods. Following this, we will conduct a 10 patient pilot study as an extension of our current Phase I trial with Dr. John Wagner at the University of Minnesota to evaluate the safety and feasibility of overnight shipment of cells. 2) In a concurrent pilot study to be conducted locally, determine whether infusion of the expanded cell product, which is devoid of T cells, can be infused without need for HLA- matching. In this study, patients undergoing conventional CBT will receive CB progenitors previously expanded from a fresh CB unit and then cryopreserved for future use as an "off-the-shelf" product. If successful, this would dramatically increase patient access to this product. 3) Establish a clinical trials group and cell therapy manufacturing collaborations required to conduct a randomized, multi-institutional trial in two years time via the BMT-CTN and PACT if possible. PUBLIC HEALTH RELEVANCE: Patients undergoing a cord blood transplant, who are often of minority or mixed ethnicity background, are at increased risk of infection and early death following the transplant due to the significant delay in white blood cells recovery (in particular, neutrophils) that these patients experience. However, using a novel culture methodology, we have demonstrated for the first time the ability to generate increased numbers of cells from a single unit of cord blood that are capable of rapid neutrophil recovery when infused in the clinical setting. Further development of this product to confirm our initial promising results requires additional clinical trials that, if successful, could change the way cord blood transplantation is performed.

描述（由申请人提供）：为了克服用脐带血移植后发生的嗜中性粒细胞恢复的显着延迟，我们成功地开发了一种新型且临床上可行的方法，利用一种工程化的Notch配体来体内生成CD34+细胞的数量增加。目前正在进行一项使用Notch介导的CB祖细胞扩展的CB祖细胞的I期临床试验中，目前正在接受髓质脐带血移植（CBT）。该试验的结果不仅证明了这种方法的安全性，而且更重要的是，第一次证明，在输注过体内扩展的造血祖细胞后，可以实现髓样快速的植入。在接受扩展细胞扩张的患者中，与中位数为26天的中位时间（P = 0.002）相比，在接受相同治疗但两个非操纵CB单元的同时同时进行的同时同时同时同时同时进行了26天（P = 0.002），在接受扩展细胞的患者中，中值时间的中位时间显着减少至16天。因此，尽管迄今为止接受治疗的患者人数很少（n = 10），但已清楚地证明了对髓样恢复的时间的重大影响，这种方法的安全性和临床可行性也是如此。 现在，这种方法的进一步发展取决于确定临床功效，这将需要随机的多机构试验。在进行此类试验之前，需要解决几个关键问题，包括制造和安全地运送到外部中心的能力，建立适当的临床试验和细胞疗法制造协作小组（S）进行未来II期随机的多个阶段多机构多机构试验，并确定对Vivo的HLA匹配需求进行Vivo供临床扩张的产品。我们的目标是，在两年资金期结束时，我们将做好准备并准备开始进行关键的II期研究。 具体而言，我们现在提出以下目的：1）确定将扩展的细胞运送到外部中心输注的方法，包括对我们已建立的拟议方法的鼠模型中对体内重现能力的临床前评估。此后，我们将与明尼苏达大学的约翰·瓦格纳（John Wagner）博士进行10次患者试验研究，以扩展我们当前的I期试验，以评估过夜式销售细胞的安全性和可行性。 2）在一项同时进行的试点研究中，确定是否可以注入不需要T细胞的扩展细胞产物的输注而无需HLA-HA-匹配。在这项研究中，接受常规CBT的患者将接受以前从新鲜的CB单元扩展的CB祖细胞，然后冷冻保存，以将来用作“现成”产品。如果成功，这将大大增加患者对该产品的机会。 3）建立一个在两年内通过BMT-CTN和PACT在两年内进行随机，多机构试验所需的临床试验组和细胞疗法制造协作。 公共卫生相关性：经常具有少数族裔或混合种族背景的脐带血移植的患者因白血细胞恢复（尤其是中性粒细胞）经历的延迟而受到感染的风险增加，并且在移植后具有早期死亡的风险。但是，使用一种新颖的培养方法，我们首次证明了从单个单位血液中产生增加细胞数量的能力，这些能力在临床环境中注入时能够快速中性粒细胞恢复。该产品的进一步开发以确认我们最初的有希望的结果需要其他临床试验，如果成功，可以改变脐带血移植的方式。