Novel Immunotherapeutic Approaches and Tools Utilizing Allogeneic T Cells

异基因造血干细胞移植（alloSCT）是一种成熟的治疗血液系统恶性肿瘤的方法。 尽管具有治疗潜力，但alloSCT因缺乏人类白细胞抗原（HLA）匹配而受到限制 供者对大多数患者和显着的毒性，特别是GVHD和机会性感染。我们有 在两项现有的临床试验中使用高剂量的移植后环磷酰胺（Cy）， 非清髓性预处理后HLA不匹配的alloSCT， HLA匹配的alloSCT后药物免疫抑制延长。这两项试验都表明 急性和慢性GVHD的发生率非常低，严重机会性感染的发生率低， 治疗相关死亡率低。本提案的中心目标是描述 高剂量、移植后Cy对alloSCT后同种异体反应性和免疫重建影响，以及其用途 高剂量移植后Cy抑制移植物排斥和移植物抗宿主病（GVHD） 致死条件和部分HLA不匹配的alloSCT。我们的研究是基于这样的假设， 移植后Cy选择性地诱导增殖的同种异体反应性T细胞的耐受，同时保留静息T细胞。 负责对感染免疫的T细胞;即移植后Cy诱导选择性体内免疫 同种异体耗竭因此，我们提出了以下具体目标：（1）描述 移植后Cy诱导的耐受，（2）表征移植后Cy对移植后免疫耐受的影响。 T细胞和抗原特异性T细胞的重建，和（3）进行清髓性的II期试验， 具有T细胞充满移植物和移植后Cy.总的职业目标 候选人将成为临床免疫治疗的独立翻译研究者。立即 职业目标是（1）发展基于免疫学的实验室分析的专业知识，（2）发展专业知识 在设计和实施治疗晚期恶性血液病患者的临床试验中。一 由经验丰富的调查人员组成的指导委员会将指导候选人完成一系列分阶段的 研究努力在一个丰富的，学术环境强烈致力于候选人。 相关性（参见说明）： 该建议利用一种新的移植后免疫抑制方案，以最大限度地减少移植相关的免疫反应。 并发症提出的目标是“建立部分HLA不匹配的BMT作为一线治疗的关键 替代供体选择和确定新的GVHD预防金标准。这项建议是 为未来新的和广泛适用的免疫疗法奠定基础。

Allogeneic stem cell transplantation (alloSCT) is a well-established therapy for hematologic malignancies. Despite its curative potential, alloSCT is limited by the lack of human leukocyte antigen (HLA)-matched donors for most patients and by significant toxicity, especially GVHD and opportunistic infection. We have used high dose, post-transplantation cyclophosphamide (Cy) in two existing clinical trials to enable partially HLA-mismatched alloSCT after nonmyeloablative conditioning and to eliminate the requirement for prolonged pharmacologic immunosuppression after HLA-matched alloSCT. Both of these trials have shown remarkably low incidences of acute and chronic GVHD, a low incidence of serious opportunistic infection, and low treatment-related mortality. The central objectives of this proposal are to characterize the effects of high-dose, post-transplantation Cy on alloreactivity and immune reconstitution after alloSCT, and to use high-dose, post-transplantation Cy to suppress graft rejection and graft-versus-host disease (GVHD) after lethal conditioningand partially HLA-mismatched alloSCT. Our studies are based on the hypothesis that post-transplantation Cy selectively induces tolerance in proliferating, alloreactive T cells while sparing resting T cells responsible for immunity to infection; i.e. post-transplantation Cy induces selective invivo allodepletion. Accordingly, we propose the following specific aims: (1) Characterize the mechanism(s) of post-transplantation Cy-induced tolerance, (2) Characterize the effects of post-transplantation Cy on the reconstitution of T cells and antigen-specific T cells, and (3) Conduct a phase II trial of myeloablative, haploidentical BMT with T cell replete grafts and post-transplantation Cy. The overall career goal of the candidate is to become an independent translational investigator in clinical immunotherapy. Immediate career goals are to (1) develop expertise in immunology based laboratory assays and (2) develop expertise in the design and conduct of a clinical trial to treat patients with advanced hematologic malignancies. A mentoring committee comprising seasoned investigators will guide the candidate through a series of phased research endeavors in a rich, academic environment strongly committed to the candidate. RELEVANCE (See instructions): This proposal utilizes a novel regimen of post-transplant immunosuppression to minimize transplant-related complications. The aims proposed are' crucial for establishing partially HLA-mismatched BMT as a first-line alternative donor option and identifying a new gold standard for GVHD prophylaxis. This proposal is the foundation for future novel and widely applicable immunotherapies.