Novel Cord Blood-Derived Cellular Therapies

总体概述 脐带血（CB）是造血祖细胞（HPC）的宝贵来源， 治疗各种恶性和非恶性疾病的个体， 缺少合适的HLA匹配的捐赠者最终，CB移植的未来将取决于 该程序的某些局限性也得到了解决，包括CB中HPC的数量相对较少 收集;植入和免疫恢复的时间较慢;以及明显降低的能力。 的CB细胞回家骨髓。因此，P01赠款支持的初始长期目标 研究是为了提高CB移植对血液恶性肿瘤的疗效。虽然仍 专注于该计划的几个原始目标，这种竞争性的更新申请现在 包括基于CB的疗法，有可能将我们研究的益处扩展到 非移植环境。这一新出现的重点导致提案标题的改变， “改善脐带血移植”到“新的脐带血细胞疗法”，并到一个新的整体 中心假设：CB衍生的HPC可以以多种方式离体修饰，以改善其生物学特性。 不仅是CB移植的结果，而且是一般细胞疗法的结果。调查人员选择了 这次更新工作代表了四个研究项目和三个核心服务，都有出色的记录 在移植医学，细胞治疗，免疫学，成人和儿科的合作研究， 血液学-预测协同作用，以实现此处概述的特定目标。项目 1（E.什帕尔河Sackstein）寻求通过在MSC介导的细胞因子中结合 用CB细胞的外岩藻糖基化进行扩增，以提高HPC数量和归巢能力，并减少 或使用CB组织来源的MSC消除GvHD。在项目2（C. Bollard，D.尼克松），安全， 输注体外扩增的CB衍生的T细胞靶向四种病毒的可行性和有效性将是 研究人员在接受CB移植治疗耐药恶性血液病的患者中进行了测试 还将确定是否可以将高效病毒特异性T细胞（VST）策略扩展到 移植后艾滋病的预防项目3（K. Rezvani，J.橙子）计划前瞻性地 评估一个有趣的假设，即CB-自然杀伤细胞的持久性和活性， 通过基因修饰这些细胞，可以增强淋巴恶性肿瘤，而没有过度的毒性， 以表达CD 19特异性CAR和IL-15。最后，项目4（J. Molldrem，G. Al-Atrash，Q.马）将 继续开发一种新的策略，通过重定向T- HLA-A2限制性PR 1表位的细胞特异性，使用动物模型和人体试验。

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.