Allogeneic stem cell transplant with grafts depleted of naive T cells for leukemi

应聘者描述(申请人提供)：应聘者的职业目标是成为翻译免疫学实验室的首席研究员，该实验室将开发新的方法来提高接受异基因造血干细胞移植(HCT)的白血病患者的无病存活率。具体地说，候选人渴望开发免疫疗法来增强移植物抗白血病(GVL)效应，从而降低HCT后的复发率，以及减少包括移植物抗宿主病(GVHD)在内的危及生命的HCT免疫并发症的策略。在短期内，候选人的目标是获得将她的研究转化为临床的经验，作为临床试验的首席研究员，该临床试验名为“选择性去除异基因外周血干细胞移植中的CD45RA+T细胞以预防GVHD的多中心第二阶段研究(FHCRC协议2222)”，发展进一步的抗原鉴定技能，并在设计、实施、解释和资助她的研究方面独立。计划的研究活动包括进行和评估初始T细胞耗尽的临床试验和相关的免疫重建研究，以及产生人类次要组织相容性(H)抗原库的抗原发现研究。候选人将接受临床试验、高级流式细胞术、免疫监测统计分析、遗传连锁分析和全基因组关联研究方面的培训。研究和培训活动将主要在弗雷德·哈钦森癌症研究中心进行，该中心是进行翻译和临床研究的绝佳环境，特别是在HCT领域。候选人将由斯坦利·里德尔博士指导，他是一位经验丰富、成功的导师，在翻译免疫学、免疫疗法和HCT领域有着杰出的职业生涯。申请者参与了临床试验开发的所有阶段，这是一项新的、首个人类研究，将为GVHD的免疫生物学和含有有限数量记忆T细胞的干细胞移植受者保护性T细胞免疫的恢复提供见解。这种方法可能为异基因血细胞移植提供一种新的方式，减少移植物抗宿主病和更好的免疫重建。目标3中提出的研究将采用发现微小H抗原的新策略，并有助于为未来针对HCT后白血病复发问题的免疫治疗方法奠定基础。其具体目的是：1.确定去除TN的干细胞移植在人类白细胞抗原相合的血缘关系干细胞移植受者中是否安全并减少移植物抗宿主病。2.探讨去除TN的HLA相合相关干细胞移植受者病原体特异性TM细胞和TN细胞的重建情况。3.建立在包括急性白血病在内的造血细胞上选择性表达的与流行的HLA等位基因相关的新型微小H抗原文库。

DESCRIPTION (provided by applicant): The candidate's career goal is to become a principal investigator of a translational immunology laboratory that will develop new approaches to improve the disease-free survival of patients with leukemia that receive allogeneic hematopoietic stem cell transplantation (HCT). Specifically, the candidate aspires to develop immunotherapies to augment the graft versus leukemia (GVL) effect and thereby reduce the rates of relapse following HCT, and strategies to reduce the life-threatening immunological complications of HCT including graft versus host disease (GVHD). In the immediate term, the candidate aims to gain experience in translating her research to the clinic as the Principal Investigator of the clinical trial entitled "A Multi-center Phase II Study of Selective Depletion of CD45RA+ T Cells from Allogeneic Peripheral Blood Stem Cell Grafts for the Prevention of GVHD (FHCRC Protocol 2222)", to develop further skills in antigen identification, and to become independent in designing, conducting, interpreting and funding her research. The research activities planned include the conduct and evaluation of the clinical trial of naive T cell depletion and associated immune reconstitution studies, and antigen discovery studies to generate a library of human minor histocompatibility (H) antigens. The candidate will obtain training in clinical trials, advanced flow cytometry, statistical analysis of immune monitoring, genetic linkage analysis and genome-wide association studies. The research and training activities will be primarily conducted at the Fred Hutchinson Cancer Research Center which is a superb environment for translational and clinical research, particularly in the field of HCT. The candidate will be mentored by Dr. Stanley Riddell, an experienced and successful mentor who has a distinguished career in the fields of translational immunology, immunotherapy and HCT. The applicant participated in all phases of development of the clinical trial, which is a novel, first-in-human study that will provide insights into the immunobiology of GVHD and the recovery of protective T cell immunity in recipients of stem cell grafts that contain a limited number of memory T cells. This approach may result in a new modality for allogeneic HCT with less GVHD and better immune reconstitution. The studies proposed in Aim 3 will employ new strategies for minor H antigen discovery and assist in laying the foundation for future immunotherapeutic approaches to the problem of relapse of leukemia after HCT. The specific aims are: 1. To determine whether transplantation of stem cell grafts depleted of TN is safe and reduces GVHD in HLA identical related donor stem cell transplant recipients. 2. To evaluate reconstitution of pathogen-specific TM and TN cells in recipients of HLA matched related stem cell grafts depleted of TN. 3. To develop a library of novel minor H antigens that are expressed selectively on hematopoietic cells including acute leukemia and presented in association with prevalent HLA alleles.