Novel Immunotherapeutic Approaches and Tools Utilizing Allogeneic T Cells

描述（由申请人提供）：异源性干细胞移植（alloSCT）是一种成熟的血液恶性肿瘤治疗方法。尽管具有治疗潜力，但同种异体细胞移植受到大多数患者缺乏人类白细胞抗原（HLA）匹配供体和显著毒性（特别是GVHD和机会性感染）的限制。我们已经在两项现有的临床试验中使用了高剂量的移植后环磷酰胺（Cy），以在非清髓性条件下实现部分hla不匹配的同种异体细胞移植，并消除hla匹配的同种异体细胞移植后长时间的药理学免疫抑制需求。这两项试验都表明，急性和慢性GVHD的发病率非常低，严重机会性感染的发病率很低，治疗相关死亡率也很低。本研究的中心目标是表征移植后高剂量Cy对同种异体移植后同种异体反应性和免疫重建的影响，并使用高剂量移植后Cy抑制致死性调节和部分hla不匹配的同种异体移植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：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，同时保留负责免疫感染的静息T细胞；即移植后Cy诱导选择性体内异体消耗。为此，我们提出以下具体目标：(1)确定移植后Cy诱导耐受的机制；(2)确定移植后Cy对T细胞和抗原特异性T细胞重构的影响；(3)开展一项清髓、单倍体同源BMT与T细胞充满移植物和移植后Cy的II期试验。候选人的总体职业目标是成为一名独立的临床免疫治疗转化研究者。近期的职业目标是：(1)在基于免疫学的实验室分析方面发展专业知识；(2)在设计和实施治疗晚期血液恶性肿瘤患者的临床试验方面发展专业知识。由经验丰富的研究人员组成的指导委员会将在丰富的学术环境中指导候选人完成一系列分阶段的研究工作。

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.