Enhancement of Lympho-Hematopoietic Recovery after UCBT

UCBT 后增强淋巴造血恢复

• 批准号: 7917906
• 负责人: John E. Wagner
• 金额: $ 98.91万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7917906
• 关键词: Acute Graft Versus Host Disease; Address; Adoptive Transfer; Adult; Age; Alloantigen; Allogenic; Antigen-Presenting Cells; Antigens; Back; Biological; Cell Transplantation; Cell Transplants; Cells; Child; Clinical; Clinical Trials; Convalescence; Cyclic GMP; Cyclosporine; Data; Development; Dose; Effector Cell; Engraftment; Environment; Equilibrium; Eragrostis; Funding; Goals; Grant; Half-Life; Hematopoietic; Human; Immune; Immunity; Immunosuppression; Immunosuppressive Agents; In Vitro; Incidence; Infection; Infusion procedures; Kilogram; Laboratory Animals; Maximum Tolerated Dose; Measures; Methodology; Methods; Modeling; Modification; Morbidity - disease rate; Mus; Outcome; Patients; Phase; Phase I Clinical Trials; Population; Positioning Attribute; Preparation; Prevention; Property; Prophylactic treatment; Publishing; Quality of life; Race; Recovery; Regimen; Regulatory T-Lymphocyte; Relapse; Reporting; Research; Research Personnel; Risk; Role; Safety; Series; Severities; Sirolimus; Source; Stem cells; System; T-Lymphocyte; Testing; Therapeutic; Thymic epithelial cell; Transplant Recipients; Transplantation; Treatment Protocols; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; Weight; base; cell injury; experience; graft vs host disease; high risk; improved; in vivo; mortality; mycophenolate mofetil; novel; novel strategies; older patient; patient population; pre-clinical; preclinical study; prevent; progenitor; prophylactic; randomized trial; reconstitution; research clinical testing; response; scale up; stem; thymocyte; tumor progression

The central hypothesis of Project 1 is that a combination of umbilical cord blood (UCB)-derived T regulatory (Treg) cells and thymic progenitors (Tprog) will optimize the safety of UCB by eliminating the risk of severe acute GVHD and enhancing immune recovery. During the current funding period, we initiated the first-inhuman clinical trials with UCB Treg after having developed an expansion culture methodology that routinely yielded Treg that were highly suppressive both in vitro and in vivo using a xenogenic GVHD murine model. During this period, we also evaluated the effect of commonly used immunosuppressive agents on Treg at concentrations routinely achievable in transplant recipients. On the basis of these results, we initiated a second clinical trial with UCB-Tregs using rapamycin (Rapa) rather than Cyclosporin A in combination with mycophenolate mofetil (MMF) to optimize in vivo expansion and half life as well as potency. Over the next grant period, our goal is to develop an integrated, cell-based approach that will ultimately reduce the risk of acute GVHD, permit a reduction in the need for prolonged posttransplant immunosuppression, and enhance the pace of immune reconstitution. To accomplish these goals, we will first establish the maximum tolerable dose of Treg using newly developed improved methods for large scale Treg manufacture, and then demonstrate the potency of partially HLA matched Treg in prevention and ¿off the shelf¿ HLA unmatched Treg in treatment of acute GVHD. We will also test novel approaches to T cell immune reconstitution by determining the optimal balance of Treg and T effector cells in the UCB graft without posttransplant GVHD prophylaxis, and subsequently adding Tprog to this treatment platform to enhance thymopoiesis and T cell immune reconstitution. At the conclusion of these studies, we will have demonstrated the safety profile and potency of UCB Treg and established a new treatment paradigm without pharmacologic immunosuppression for evaluating safety and efficacy of Tprog.

项目1的中心假设是，脐带血（UCB）衍生的T调节（Treg）细胞和胸腺祖细胞（TPROG）的结合将通过消除严重急性GVHD的风险和增强免疫发现来优化UCB的安全性。在当前的融资期间，我们在开发了一种扩张培养方法后，通过UCB Treg进行了第一次人口临床试验，该方法通常使用异种GVHD鼠模型产生了体外和体内高度抑制的Treg。在此期间，我们还评估了通常在移植受体中成功成功的浓度的常用免疫抑制剂对Treg的影响。根据这些结果，我们使用雷帕霉素（RAPA）而不是环孢菌素A与霉酚酸酯Mofetil（MMF）结合使用UCB-Treg进行了第二次临床试验，以优化体内扩张和半寿命以及效力。在下一个赠款期间，我们的目标是开发一种基于细胞的综合方法，最终将降低急性GVHD的风险，允许减少长期移植后免疫抑制的需求，并加强免疫重新结构的速度。为了实现这些目标，我们将使用新开发的大规模Treg制造的改进方法建立最大耐受剂量的Treg，然后证明部分HLA匹配的Treg在预防方面的效力，并在架子上脱离了HLA无与伦比的Treg在急性GVHD治疗方面。我们还将通过确定UCB移植物中Treg和T效应细胞在没有移植后GVHD预防的情况下的最佳平衡来测试T细胞免疫重建的新方法，然后将TPROG添加到此治疗平台中，以增强胸腺硫代细胞和T细胞 免疫重建。在这些研究结束时，我们将证明UCB Treg的安全性和效力，并建立了一个新的治疗范式，而没有药理免疫抑制，以评估TPROG的安全性和效率。