Novel Immunotherapeutic Approaches and Tools Utilizing Allogeneic T Cells

异基因干细胞移植是治疗恶性血液病的一种行之有效的疗法。 尽管异基因干细胞移植具有治疗潜力，但由于缺乏匹配的人类白细胞抗原(HLAs)而受到限制。 供者对大多数患者有明显的毒性，尤其是移植物抗宿主病和机会性感染。我们有 在两项现有的临床试验中使用了大剂量、移植后的环磷酰胺(Cy)，使部分 非清髓性预适应后进行不相合的异基因干细胞移植，并消除对 人类白细胞抗原相合异基因干细胞移植后药物免疫抑制时间延长。这两项试验都表明 急性和慢性移植物抗宿主病的发生率非常低，严重机会性感染的发生率很低， 和较低的治疗相关死亡率。这项提案的中心目标是描述 大剂量、移植后环磷酰胺对异基因干细胞移植后同种异体反应性和免疫重建的影响 移植后大剂量环磷酰胺抑制移植排斥反应和移植物抗宿主病(GVHD) 致死性条件和部分HLA不相合的异基因干细胞移植。我们的研究是基于这样一个假设： 移植后Cy选择性诱导增殖的同种异体反应性T细胞耐受 负责感染免疫的T细胞；即移植后Cy在体内诱导选择性 分配耗尽。因此，我们提出了以下具体目标：(1)刻画(S)的作用机制 移植后Cy诱导的免疫耐受，(2)表征移植后Cy对 T细胞和抗原特异性T细胞的重建，以及(3)进行清髓剂的II期试验， 半相合骨髓移植与T细胞完全移植及移植后细胞周期。职业生涯的总体目标是 候选人将成为临床免疫治疗领域的独立翻译研究员。立马 职业目标是(1)发展基于免疫学的实验室分析方面的专业知识和(2)发展专业知识 参与设计和实施一项治疗晚期血液系统恶性肿瘤患者的临床试验。一个 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 研究工作在丰富的学术环境中进行，坚定地致力于应聘者。 相关性(请参阅说明)： 这项建议利用了一种新的移植后免疫抑制方案，将移植相关的免疫抑制降至最低。 并发症。提出的目标对于建立部分人类白细胞抗原不相合的骨髓移植作为一线至关重要 替代捐赠者选择，并确定预防GVHD的新黄金标准。这项建议是 为未来新的和广泛应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.