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

描述（由申请人提供）：为了克服脐带血移植（CB）后中性粒细胞恢复的显著延迟，我们已经成功开发了一种新的临床可行的方法，利用工程Notch配体来体外生成更多的CD34+细胞。目前正在进行一项I期临床试验，利用notch介导的扩展CB祖细胞治疗接受清髓脐带血移植（CBT）的患者。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了在输注体外扩增的造血祖细胞后可以实现快速骨髓移植。在接受扩增细胞治疗的患者中，观察到中性粒细胞绝对计数达到500/<ml的中位时间仅为16天，而在同时进行的20例接受相同治疗但使用两个非操纵CB单位的患者中，中位时间为26天（p=0.002）。因此，尽管迄今为止接受治疗的患者数量很少（n=10），但已经清楚地证明了对骨髓恢复时间的显着影响，以及该方法的安全性和临床可行性。该方法的进一步发展现在取决于临床疗效的确定，这将需要一项随机的多机构试验。在开始这样的试验之前，需要解决几个关键问题，包括制造和安全运送细胞到外部中心的能力，建立适当的临床试验和细胞治疗制造合作小组来进行未来的II期随机多机构试验，以及确定体外扩展产品用于临床使用的hla匹配需求。我们的目标是，在两年的资助期结束时，我们将准备好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)确定将扩增细胞运送到外部中心进行输注的方法，包括在我们所建立的小鼠模型中对体内再生能力进行临床前评估。在此之后，我们将进行一项10名患者的试点研究，作为我们目前与明尼苏达大学的John Wagner博士进行的一期试验的延伸，以评估隔夜运送细胞的安全性和可行性。2)在一项将在当地进行的同步中试研究中，确定是否可以输注不含T细胞的扩增细胞产物，而无需进行HLA匹配。在这项研究中，接受常规CBT治疗的患者将接受从新鲜脑脊膜细胞中扩增的脑脊膜祖细胞，然后作为“现成”产品冷冻保存以备将来使用。如果成功，这将极大地增加患者使用该产品的机会。3)如果可能的话，建立一个临床试验组和细胞治疗制造合作，在两年内通过BMT-CTN和PACT进行随机的多机构试验。

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.