IMPROVING CORD BLOOD TRANSPLANTATION

描述（由申请人提供）：脐带血（CB）作为没有人类白细胞抗原（HLA）匹配供体的患者的替代移植来源的引入是干细胞移植领域的一个明显突破。然而，持续低剂量的CB祖细胞，导致移植和免疫重建延迟，不可接受的感染率和癌症患者的高复发率，限制了该手术的使用，特别是在成人中。因此，该提案的长期目标是通过将令人信服的实验室发现转化为临床试验来改善CB移植的结果，所有这些都在多学科p01资助的框架内。该项目的研究人员代表4个研究项目和4个核心服务，在癌症免疫学、病毒免疫学、CB移植、过继t细胞治疗和干细胞生物学方面有很强的合作研究记录，预测在追求这里概述的目标中广泛的（和协同的）相互作用。项目1将验证输注前在骨髓基质细胞上扩增的CB祖细胞比未处理的CB细胞移植更快的假设，并将进一步评估用focusyltransferase治疗CB祖细胞作为改善骨髓归巢和移植的新手段。项目2询问是否输注针对多种病毒的cb衍生的细胞毒性T细胞（ctl）将提供广泛的保护，以防止移植后病毒感染，而项目3将使用嵌合抗原受体（CAR）指导这些病毒特异性ctl的特异性，针对肿瘤相关抗原CD19，以努力靶向恶性B细胞和病毒。最后，在Project 4中，我们将利用CB来源的CTL识别髓系白血病上异常表达的PR1抗原的能力，来确定接受CB移植的髓系白血病患者接受pr特异性CTL治疗的可行性和潜在疗效。最终，通过p01机制产生的信息将产生一个单一的、全面的CB移植计划，该计划将克服目前该手术的大多数局限性，使其成为大量成人和儿童癌症患者的现实选择。

DESCRIPTION (provided by applicant): The introduction of cord blood (CB) as an alternative graft source for patients without a human leukocyte antigen (HLA) matched donor was a clear breakthrough in the field of stem cell transplantation. Yet, consistently low doses of CB progenitor cells, resulting in delayed engraftment and immune reconstitution, unacceptable rates of infection, and high rates of relapse in CB recipients with cancer, have restricted the use of this procedure, especially in adults. Hence, the long-range goal of this proposal is to improve the outcome of CB transplantation by translating compelling laboratory findings into clinical trials, all within the framework of a multidisciplinary P01grant. The investigators in this program, representing 4 research projects and 4 Core services, have strong records of collaborative investigation in cancer immunology, viral immunology, CB transplantation, adoptive T-cell therapy, and stem cell biology - predicting extensive (and synergistic) interactions in pursuit of the goals outlined here. Project 1 will test the hypothesis that CB progenitors expanded on marrow stromal cells prior to infusion will engraft more rapidly than unmanipulated CB cells, and will further evaluate treatment of CB progenitors with fucosyltransferase as a novel means to improve bone marrow homing and engraftment. Project 2 asks if the infusion of CB-derived cytotoxic T cells (CTLs) targeting multiple viruses will provide broad protection against post-transplant viral infections, while Project 3 will direct the specificity of these virus-specific CTLs, using a chimeric antigen receptor (CAR), to the tumor-associated antigen CD19 in an effort to target malignant B cells as well as viruses. Finally, in Project 4, the ability of CB-derived CTLs to recognize the PR1 antigen aberrantly expressed on myeloid leukemias will be exploited to determine the feasibility and potential efficacy of PRI-specific CTL therapy in patients with myeloid leukemia undergoing CB transplantation. Ultimately, the information generated through this P01mechanism should yield a single, comprehensive plan of CB transplantation that will overcome most current limitations of this procedure, making it a realistic option for larger numbers of adult and childhood cancer patients.