Novel Cord Blood-Derived Cellular Therapies

总体计划摘要 脐带血(CB)是一种重要的造血祖细胞(HPC)来源 治疗范围广泛的恶性和非恶性疾病患者 会缺乏合适的人类白细胞抗原配型的捐献者。最终，脐带血移植的未来将取决于移植的效果如何 讨论了此程序的某些限制，包括CB中的HPC数量相对较少 移植和免疫恢复的时间较慢；以及能力明显下降 将脐带血细胞移植到骨髓中。因此，这一P01赠款支持的最初长期目标 研究旨在提高脐带血移植治疗恶性血液病的疗效。虽然还在 专注于该计划的几个原始目标，这一竞争性续订申请现在 包括基于CB的疗法，有可能将我们研究的好处扩展到 非移植环境。这种新出现的强调导致了提案标题的更改，从 从“改进脐血移植”到“新的脐血细胞疗法”，再到一个新的整体 中心假设：CB来源的HPC可以在体外以不同的方式进行修饰，以改善 不仅是脐带血移植的结果，而且总体上也是细胞疗法的结果。调查人员选择了 对于这一更新工作，代表了四个研究项目和三个核心服务，所有这些项目都有出色的记录 在移植医学、细胞治疗、免疫学以及成人和儿科领域的合作研究 血液学-预测协同作用，以追求这里概述的特定目标。项目 1(E.Shpall，R.Sackstein)寻求通过在MSC介导的情况下结合 用胞外糖基化扩增脐血细胞，以增加HPC数量和归巢能力，并减少 或使用脐带血组织来源的间充质干细胞来消除GvHD。在项目2(C.Bollard，D.Nixon)中，安全， 针对四种病毒的体外扩增CB来源的T细胞输注的可行性和有效性将是 研究人员在接受脐带血移植治疗耐药恶性血液病的患者中进行了测试 也将决定高效的病毒特异性T细胞(VST)策略是否可以扩展到 移植后艾滋病毒的预防。项目3(K.Rezvani，J.Orange)计划前瞻性地 评估一个耐人寻味的假设，即CB-自然杀伤细胞对 淋巴系统恶性肿瘤可以通过对这些细胞进行遗传修饰来增强，而不会产生不必要的毒性。 表达CD19特异性CAR和IL-15。最后，项目4(J.Molldrem，G.Al-Atrash，Q.Ma)将 继续开发一种新的策略来降低髓系白血病的复发率，方法是将T- 使用动物模型和人体试验，对人类白细胞抗原A2限制的PR1表位具有细胞特异性。

OVERALL PROGRAM SUMMARY Umbilical cord blood (CB) is a valuable source of hematopoietic progenitor cells (HPCs) for the treatment of a broad range of malignant and nonmalignant disorders in individuals who otherwise would lack a suitable HLA-matched donor. Ultimately, the future of CB transplant will rest on how well certain limitations of this procedure are addressed, including the relatively low numbers of HPCs in CB collections; the slower times to engraftment and immune recovery; and the apparent reduced ability of CB cells to home to bone marrow. Hence, the initial long-term goal of this P01 grant-supported research was to enhance the efficacy of CB transplant for hematologic malignancies. Although still focused on several of the program's original objectives, this competitive renewal application now encompasses CB-based therapies with the potential to extend the benefits of our research to nontransplant settings. This emerging emphasis has led to a change in the title of the proposal, from “Improving Cord Blood Transplantation” to “Novel Cord Blood Cellular Therapies,” and to a new overall central hypothesis: that CB-derived HPCs can be modified in diverse ways ex vivo to improve the outcomes not only of CB transplant but also of cellular therapies in general. The investigators chosen for this renewal effort represent four research projects and three Core services, all with stellar records of collaborative investigation in transplant medicine, cell therapy, immunology, and adult and pediatric hematology – predicting synergistic interactions in pursuit of the specific aims outlined here. Project 1 (E. Shpall, R. Sackstein) seeks to further enhance CB engraftment by combining, in MSC-mediated expansion with exofucosylation of CB cells to boost HPC numbers and homing capacity, and to lessen or abrogate GvHD using CB tissue-derived MSCs. In Project 2 (C. Bollard, D. Nixon), the safety, feasibility and efficacy of infusing ex vivo-expanded CB-derived T cells targeting four viruses will be tested in patients undergoing CB transplant for resistant hematologic malignancies, The investigators will also determine whether the highly effective virus-specific T-cell (VST) strategy can be extended to the prevention of HIV post-transplant. Project 3 (K. Rezvani, J. Orange) plans to prospectively assess an intriguing hypothesis that the persistence and activity of CB-natural killer cells against lymphoid malignancies can be enhanced, without undue toxicity, by genetically modifying these cells to express a CD19-specific CAR and IL-15. Finally, Project 4 (J. Molldrem, G. Al-Atrash, Q. Ma) will continue to develop a novel strategy to lower relapse rates in the myeloid leukemias by redirecting T- cell specificity to the HLA-A2-restricted PR1 epitope, using both animal models and human trials.