Novel Cord Blood-Derived Cellular Therapies

新型脐带血细胞疗法

• 批准号: 10478141
• 负责人: Catherine M. Bollard
• 金额: $ 254.99万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-22 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10478141
• 关键词: AIDS prevention; Address; Adenoviruses; Adoptive Immunotherapy; Adoptive Transfer; Adult; Animal Model; BK Virus; Blood Cells; Bone Marrow; Bone Marrow Transplantation; CD19 gene; Cell Count; Cell Therapy; Cell Transplantation; Cells; Child; Clinical; Collaborations; Collection; Cytomegalovirus; Disease; Effectiveness; Engraftment; Epitopes; Frequencies; Fucosyltransferase; Funding; Future; Gene-Modified; Generations; Genetic Engineering; Goals; Grant; HIV; HLA-A2 Antigen; Hematologic Neoplasms; Hematological Disease; Hematopoietic stem cells; High-Risk Cancer; Home; Homing; Human; Human Herpesvirus 4; Immune; Immune system; Immunology; Incidence; Individual; Infection; Infusion procedures; Interleukin-15; Investigation; Life; Malignant - descriptor; Malignant Neoplasms; Malignant lymphoid neoplasm; Mediating; Medical; Mesenchymal; Mesenchymal Stem Cells; Minority; Myelogenous; Myeloid Leukemia; Natural Killer Cells; Natural regeneration; Non-Malignant; Oranges; Patients; Pediatric Hematology; Procedures; Publications; Records; Recovery; Recurrence; Relapse; Research; Research Personnel; Research Project Grants; Research Support; Residual state; Resistance; Resources; Rest; Services; Ships; Source; T-Cell Immunologic Specificity; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Toxic effect; Transplantation; Tumor Antigens; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; Virus; Virus Diseases; Work; anticancer research; antigen-specific T cells; base; cancer cell; cancer therapy; chemotherapy; chimeric antigen receptor; chimeric antigen receptor T cells; design; genetically modified cells; graft vs host disease; improved; improved outcome; innovation; insight; leukemia/lymphoma; minority patient; novel; novel strategies; pathogen; pediatric patients; peripheral blood; personalized immunotherapy; post-transplant; prevent; primitive cell; programs; prospective; racial and ethnic; racial minority; safety and feasibility; stem cells; transplantation medicine; treatment choice; tumor

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.

总体计划概要 脐带血（CB）是造血祖细胞（HPC）的宝贵来源 治疗患有其他疾病的个体的多种恶性和非恶性疾病 最终，CB 移植的未来将取决于其效果如何。 该程序的某些局限性得到解决，包括 CB 中 HPC 数量相对较少 收集；植入和免疫恢复时间较慢，能力明显下降； 因此，这项 P01 拨款支持的最初长期目标是 CB 细胞归巢。 研究旨在增强 CB 移植对血液恶性肿瘤的疗效，尽管仍然如此。 专注于该计划的几个原始目标，现在这个具有竞争力的续订应用程序 包括基于 CB 的疗法，有可能将我们研究的益处扩展到 这种新兴的强调导致了提案标题的变化，从 从“改善脐带血移植”到“新型脐带血细胞疗法”，以及新的整体 中心假设：CB 衍生的 HPC 可以通过多种方式离体进行修饰，以改善 研究人员选择的结果不仅包括CB移植的结果，还包括一般细胞疗法的结果。 此次更新工作代表了四个研究项目和三个核心服务，所有这些都拥有出色的记录 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 - 预测协同相互作用以实现此处概述的具体目标项目。 1 (E. Shpall, R. Sackstein) 寻求通过在 MSC 介导的组合中进一步增强 CB 植入 通过 CB 细胞的外岩藻糖基化进行扩增，以增加 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. Nixon）中，安全性、 输注针对四种病毒的离体扩增 CB 衍生 T 细胞的可行性和功效 研究人员对接受 CB 移植治疗耐药性血液恶性肿瘤的患者进行了测试 还将确定高效的病毒特异性T细胞（VST）策略是否可以扩展到 项目 3（K. Rezvani、J. Orange）计划前瞻性地预防移植后艾滋病毒。 评估一个有趣的假设，即 CB-自然杀伤细胞的持久性和活性 通过对这些细胞进行基因改造，可以增强淋巴恶性肿瘤的治疗效果，而不会产生过度毒性 最后，项目 4（J. Molldrem、G. Al-Atrash、Q. Ma）将表达 CD19 特异性 CAR 和 IL-15。 继续开发一种新策略，通过重新定向 T-来降低髓系白血病的复发率 使用动物模型和人体试验研究细胞对 HLA-A2 限制性 PR1 表位的特异性。

项目成果

Outcomes of Second Allogeneic Hematopoietic Cell Transplantation for Patients With Acute Myeloid Leukemia.

• DOI: 10.1016/j.jtct.2021.05.007
• 发表时间: 2021-08
• 期刊: Transplantation and cellular therapy
• 影响因子: 3.2
• 作者: Yalniz FF;Saliba RM;Greenbaum U;Ramdial J;Popat U;Oran B;Alousi A;Olson A;Alatrash G;Marin D;Rezvani K;Hosing C;Im J;Mehta R;Qazilbash M;Joseph JJ;Rondon G;Kanagal-Shamanna R;Shpall E;Champlin R;Kebriaei P
• 通讯作者: Kebriaei P

General and Virus-Specific Immune Cell Reconstitution after Double Cord Blood Transplantation.

• DOI: 10.1016/j.bbmt.2015.02.017
• 发表时间: 2015-07
• 期刊: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
• 作者: Saliba RM;Rezvani K;Leen A;Jorgensen J;Shah N;Hosing C;Parmar S;Oran B;Olson A;Rondon G;Chen J;Martinez C;Hamdi A;Mehta RS;Chemaly RF;Saunders IM;Bollard CM;Shpall EJ
• 通讯作者: Shpall EJ

Controlling cytomegalovirus: helping the immune system take the lead.

• DOI: 10.3390/v6062242
• 发表时间: 2014-05-27
• 期刊: Viruses
• 作者: Hanley PJ;Bollard CM
• 通讯作者: Bollard CM

Complications of transplant for nonmalignant disorders: autoimmune cytopenias, opportunistic infections, and PTLD.

非恶性疾病移植并发症：自身免疫性血细胞减少、机会性感染和 PTLD。

• DOI: 10.1016/j.bbmt.2011.10.024
• 发表时间: 2012
• 期刊: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
• 作者: Dvorak,ChristopherC;Bollard,CatherineM;El-Bietar,Javier;Filipovich,Alexandra
• 通讯作者: Filipovich,Alexandra

Third-party umbilical cord blood-derived regulatory T cells prevent xenogenic graft-versus-host disease.

• DOI: 10.1016/j.jcyt.2013.07.009
• 发表时间: 2014-01
• 期刊: Cytotherapy
• 影响因子: 4.5
• 作者: Parmar S;Liu X;Tung SS;Robinson SN;Rodriguez G;Cooper LJ;Yang H;Shah N;Yang H;Konopleva M;Molldrem JJ;Garcia-Manero G;Najjar A;Yvon E;McNiece I;Rezvani K;Savoldo B;Bollard CM;Shpall EJ
• 通讯作者: Shpall EJ