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.

总体计划摘要 脐带血（CB）是造血祖细胞（HPC）的宝贵来源 对其他人的多种恶性和非恶性疾病的治疗 不是合适的HLA匹配供体。最终，CB移植的未来将取决于 解决了此过程的某些局限性，包括CB中的HPC的相对较低数量 收藏；植入和免疫恢复的时间较慢；以及明显降低的能力 CB细胞的骨髓。因此，该P01赠款支持的最初长期目标是 研究是为了提高CB移植对血液学恶性肿瘤的效率。虽然仍然 该计划的几个原始目标侧重于该竞争性更新应用程序 包括基于CB的疗法，有可能将我们的研究的好处扩展到 非移植设置。这种新兴的重点导致提案标题的变化，从 “改善绳索血液移植到“新型脐带血细胞疗法”，并为新的整体 中心假设：CB衍生的HPC可以通过潜水员的方式进行修改以改善 不仅是CB移植的结果，而且是细胞疗法的结果。调查人员选择了 为了这种续签工作，代表了四个研究项目和三个核心服务，所有这些都具有出色的记录 移植医学，细胞疗法，免疫学以及成人和小儿的协作研究 血液学 - 预测此处概述的特定目的的协同相互作用。项目 1（E。Shpall，R。Sackstein）试图通过在MSC介导 CB细胞的外生化膨胀以提高HPC数量和归巢能力，并降低 或使用CB组织衍生的MSC废除GVHD。在项目2（C. Bollard，D。Nixon）中，安全性， 可行性和易于注入靶向四个病毒的CB衍生的T细胞的易于添加 在接受CB移植的患者中测试了耐药性血液学恶性肿瘤 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 预防移植后艾滋病毒。项目3（K. Rezvani，J。Orange）计划前景 评估一个有趣的假设，即CB自然杀手细胞的持久性和活性反对 通过基因修饰这些细胞，可以增强淋巴恶性肿 表达CD19特异性汽车和IL-15。最后，项目4（J. Molldrem，G。Al-Atrash，Q。MA）将 继续制定一种新的策略，通过重定向T-来降低髓样白血病的中继率 使用动物模型和人类试验，对HLA-A2限制PR1发作的细胞特异性。

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

A single exercise bout enhances the manufacture of viral-specific T-cells from healthy donors: implications for allogeneic adoptive transfer immunotherapy.

• DOI: 10.1038/srep25852
• 发表时间: 2016-05-16
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Spielmann G;Bollard CM;Kunz H;Hanley PJ;Simpson RJ
• 通讯作者: Simpson RJ