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

基本信息

批准号：
7861081
负责人：
Colleen Delaney
金额：
$ 173.81万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7861081
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 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 Relative (related person)Resources Risk Safety Shipping Ships Site Staging Supportive care T-Lymphocyte Time Transplantation Treatment Protocols Umbilical Cord Blood Umbilical Cord Blood Transplantation Universities Work clinical efficacy cohort design expectation experience immunodeficient mouse model in vivo neutrophil notch protein novel preclinical evaluation preclinical study product development progenitor public health relevance reconstitution

项目摘要

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）：为了克服脐带血（CB）移植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配体进行离体生成CD34+细胞数量增加。目前正在进行一项 I 期临床试验，该试验利用 Notch 介导的扩增 CB 祖细胞对接受清髓性脐带血移植 (CBT) 的患者进行治疗。该试验的结果不仅证明了这种方法的安全性，更重要的是首次证明，输注离体扩增的造血祖细胞后可以实现快速骨髓移植。在接受扩增细胞的患者中，中性粒细胞绝对计数达到 500/<ml 的中位时间显着缩短，仅需 16 天，而同时接受扩增细胞治疗的 20 名患者的中位时间为 26 天 (p=0.002)。相同的处理，但使用两个非操纵的 CB 单元。因此，尽管迄今为止接受治疗的患者数量很少（n=10），但已清楚地证明了对骨髓恢复时间的显着影响，这种方法的安全性和临床可行性也是如此。这种方法的进一步进展现在取决于临床疗效的确定，这将需要随机多机构试验。在开始此类试验之前，需要解决几个关键问题，包括制造细胞并将其安全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以进行未来的阶段II 随机多机构试验，并确定临床使用的离体扩增产品是否需要 HLA 匹配。我们的目标是，在两年资助期结束时，我们将做好准备并完全准备好开始关键的第二阶段研究。具体来说，我们现在提出以下目标：1）确定将扩增的细胞运送到外部中心进行输注的方法，包括在我们建立的所提出方法的小鼠模型中对体内再增殖能力进行临床前评估。此后，我们将与明尼苏达大学的 John Wagner 博士一起进行一项 10 名患者的试点研究，作为当前 I 期试验的延伸，以评估隔夜运输细胞的安全性和可行性。 2) 在本地同时进行的试点研究中，确定是否可以在不需要 HLA 匹配的情况下输注不含 T 细胞的扩增细胞产品。在这项研究中，接受传统 CBT 的患者将接受先前从新鲜 CB 单元扩增的 CB 祖细胞，然后冷冻保存以供将来作为“现成”产品使用。如果成功，这将大大增加患者使用该产品的机会。 3) 如果可能的话，建立一个临床试验小组和细胞疗法生产合作，以在两年内通过 BMT-CTN 和 PACT 进行随机、多机构试验。公共卫生相关性：接受脐带血移植的患者通常是少数族裔或混合种族背景，由于白细胞恢复（特别是中性粒细胞）显着延迟，移植后感染和过早死亡的风险增加。这些患者的经历。然而，通过使用一种新颖的培养方法，我们首次证明了从单个单位的脐带血中产生更多细胞的能力，这些细胞在临床环境中输注时能够快速恢复中性粒细胞。该产品的进一步开发以证实我们最初的有希望的结果需要额外的临床试验，如果成功，可能会改变脐带血移植的进行方式。