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

描述（由申请人提供）：候选人的职业目标是成为转化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同种异体造血干细胞移植（HCT）的白血病患者的无病生存率。具体来说，候选人渴望开发免疫疗法来增强移植物抗白血病（GVL）效果，从而降低HCT后的复发率，以及减少危及生命的HCT免疫并发症（包括移植物抗宿主病（GVHD））的策略。在短期内，候选人的目标是获得将她的研究成果转化为临床试验的经验，作为临床试验的首席研究员，题为“从异体外周血干细胞移植中选择性消耗CD45RA+ T细胞预防GVHD （FHCRC协议2222）的多中心II期研究”，进一步发展抗原鉴定技能，并在设计，实施，解释和资助她的研究方面成为独立的。计划的研究活动包括进行和评估幼稚T细胞耗损的临床试验和相关的免疫重建研究，以及抗原发现研究，以产生人类次要组织相容性(H)抗原文库。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Fred Hutchinson癌症研究中心进行，该中心为转化和临床研究提供了极好的环境，特别是在HCT领域。候选人将由Stanley Riddell博士指导，他是一位经验丰富且成功的导师，在转化免疫学、免疫治疗和HCT领域有着杰出的职业生涯。申请人参与了临床试验开发的所有阶段，这是一项新颖的首次人体研究，将为GVHD的免疫生物学提供见解，并在含有有限数量记忆T细胞的干细胞移植物受体中恢复保护性T细胞免疫。这种方法可能会导致一种新的模式的同种异体HCT较少的GVHD和更好的免疫重建。Aim 3中提出的研究将采用小H抗原发现的新策略，并有助于为未来解决HCT后白血病复发问题的免疫治疗方法奠定基础。具体目标是：1。确定在HLA相同的相关供体干细胞移植受者中，TN缺失的干细胞移植物移植是否安全并降低GVHD。2. 目的：评价HLA匹配的相关干细胞移植后TN缺失受体中病原体特异性TM和TN细胞的重构。建立一个新的次要H抗原文库，这些抗原可在包括急性白血病在内的造血细胞上选择性表达，并与流行的HLA等位基因相关。

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.