Hematopoietic Progenitor Cells- Cord Blood

 描述(申请人提供)：脐带血(CB)已经成为治疗癌症的造血祖细胞(HPC)的宝贵来源，但其用途仍然受到同种异体脐血移植细胞数量有限和相对不成熟的限制。虽然已经提出了许多策略来增加脐带血细胞的植入潜力，但对于实现这一关键的对数周期目标的最佳和最有效的方法仍然没有达成一致意见。申请人的研究小组已经证明，将整个脐带血单位与间充质基质细胞(MSCs)进行体外培养将显著扩大谱系承诺的造血祖细胞，导致更快的中性粒细胞和血小板植入时间。这一进展，加上越来越多的证据表明，CB的岩藻糖基化可以改善祖细胞归巢和植入时间，导致了目前的更新申请。通过一系列迭代的临床和机制研究，申请人现在提出了三个具体目标，以使脐带血移植的结果与骨髓和外周血移植的结果一致。目的1：采用MSC体外扩增和岩藻糖化策略相结合的方法进一步促进CB的植入。这项临床试验的基本原理是，CB细胞的扩增和表面岩藻糖化似乎缩短了植入期。 通过互不重叠的机制，更有可能开展有效的协同活动，在成果方面取得有意义的进展。目的2：为了生产一种扩增的富含巨核细胞(MK)的CB产品，以产生更快的吞噬，申请人提议在扩增的CB细胞中确定在NSG小鼠模型中能够最佳地产生最佳的血小板恢复的祖细胞亚群(S)，如果实验动物研究和其他实验室发现有保证，计划进行临床试验。目的：全面描述CBT患者的免疫重建情况，并确定全身应用IL-7能否改善免疫重建。通过进行I/II期临床试验，申请者将建议测试全身应用IL-7的安全性、可行性和有效性，IL-7在T细胞发育和存活中起关键作用。该项目的成功将为操纵脐带血来源的细胞获得更大的临床优势提供手段，从而扩大脐带血移植对人类癌症治疗的影响。

 DESCRIPTION (provided by applicant): Umbilical cord blood (CB) has become a valuable source of hematopoietic progenitor cells (HPCs) for the treatment of cancer, but its utility continues to be restricted by the limited cell numbers and relative immaturity of CB allografts. Although numerous strategies have been proposed to increase the engraftment potential of CB cells, there is still no agreement over the best and most efficient way to achieve this critical log-term goal. The applicant's research group has shown that ex vivo culture of the entire CB unit with mesenchymal stromal cells (MSCs) will significantly expand lineage-committed hematopoietic progenitors, leading to faster times to neutrophil and platelet engraftment. This progress, together with emerging evidence that fucosylation of CB can improve both progenitor homing and engraftment times, has led to the current renewal application. Through a series of iterative clinical and mechanistic studies, the applicant now proposes three specific aims to bring the results of CB transplantation in line with those of bone marrow and peripheral blood transplantation. Aim 1: To further enhance the engraftment of CB by using a combination of ex vivo MSC-mediated expansion and fucosylation strategies. The underlying rationale of this clinical trial is that expansion and surface fucosylation of CB cells appear to shorten engraftment times by non-overlapping mechanisms, raising the possibility of potent synergistic activity leading to meaningful advances in outcome. Aim 2: To generate an expanded megakaryocyte (MK)-rich CB product that yields more rapid engratment, the applicant proposes to identify the progenitor subpopulation(s) among expanded CB cells that produces optimally rapid platelet recovery in an NSG mouse model, with a clinical trial planned if warranted by the experimental animal studies and other laboratory findings. Aim 3: To comprehensively characterize immune reconstitution in our CBT patients and determine whether it can be improved with systemic administration of IL- 7. By conducting a phase I/II clinical trial, the applicants will propose to est the safety and feasibility, as well as efficacy of systemic administration of IL-7, which has a pivotal role in T cell development and survival. Success in this project will provide means to manipulate CB-derived cells towards greater clinical advantage, thus broadening the impact of CB transplantation on the treatment of human cancers.