Novel Immunotherapeutic Approaches and Tools Utilizing Allogeneic T Cells

描述(申请人提供)：过敏性干细胞移植(AllSCT)是一种公认的治疗恶性血液病的方法。尽管异基因干细胞移植具有治疗潜力，但由于大多数患者缺乏人类白细胞抗原(HL A)相合的供者，以及严重的毒性，尤其是移植物抗宿主病(GVHD)和机会性感染，异基因SCT受到限制。我们在现有的两个临床试验中使用了大剂量的移植后环磷酰胺(Cy)，以使非清髓性预适应后部分HLA相合的异基因SCT成为可能，并消除了在HLA相合的异基因SCT后延长药物免疫抑制的需要。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，与治疗相关的死亡率也很低。这项建议的中心目标是表征大剂量、移植后Cy对异基因SCT后的同种异体反应和免疫重建的影响，并使用大剂量、移植后Cy来抑制致死性预适应和部分不相合的异基因SCT后的移植物排斥反应和移植物抗宿主病(GVHD)。我们的研究基于这样的假设，即移植后Cy选择性地诱导增殖的同种异体反应性T细胞耐受，而保留负责感染免疫的静止T细胞；即移植后Cy诱导体内选择性同种异体耗竭。因此，我们提出了以下具体目标：(1)研究移植后Cy诱导耐受的机制(S)；(2)研究移植后Cy对T细胞和抗原特异性T细胞重建的影响；(3)进行清髓性半相合骨髓移植与T细胞完全移植和移植后Cy的II期试验。应聘者的总体职业目标是成为临床免疫治疗领域的一名独立翻译研究员。近期的职业目标是：(1)发展基于免疫学的实验室分析方面的专业知识；(2)发展设计和实施治疗晚期恶性血液病患者的临床试验方面的专业知识。一个由经验丰富的调查人员组成的指导委员会将在一个强烈支持候选人的丰富的学术环境中指导候选人进行一系列阶段性研究工作。

DESCRIPTION (provided by applicant): Allergenic 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 conditioning and 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 in vivo 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.