Enhancement of Lympho-Hematopoietic Recovery after UCBT

项目1的中心假设是，脐带血(UCB)来源的T调节(Treg)细胞和胸腺祖细胞(Tprog)的组合将通过消除严重急性GVHD的风险和促进免疫恢复来优化UCB的安全性。在目前的资助期间，我们在开发了一种扩增培养方法后，启动了第一次非人类临床试验UCB Treg，该方法使用异种GVHD小鼠模型在体外和体内都能产生高度抑制的Treg。在此期间，我们还评估了在移植受者常规达到的浓度下，常用免疫抑制剂对Treg的影响。在这些结果的基础上，我们启动了UCB-Tregs的第二次临床试验，使用雷帕霉素(RAPA)而不是环孢素A与霉酚酸酯(MMF)联合使用，以优化体内扩展和半衰期以及效力。在下一个赠款期间，我们的目标是开发一种综合的、基于细胞的方法，最终降低急性GVHD的风险，减少移植后长期免疫抑制的需要，并加快免疫重建的步伐。为了实现这些目标，我们将首先使用新开发的大规模Treg制造的改进方法来确定Treg的最大耐受量，然后证明部分相合的Treg在预防和现成的人类白细胞抗原不匹配Treg在治疗急性GVHD中的有效性。我们还将测试T细胞免疫重建的新方法，通过确定脐带血移植物中Treg和T效应细胞的最佳平衡，而不是移植后GVHD预防，并随后将Tprog添加到该治疗平台以增强胸腺生成和T细胞 免疫重建。在这些研究的结论中，我们将证明UCB Treg的安全性和有效性，并建立一种新的治疗范例，无需药物免疫抑制，以评估Tprog的安全性和有效性。

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.