Minor Histocompatibility Antigen T Cell Targeting in Acute Myeloid Leukemia

急性髓性白血病中的次要组织相容性抗原 T 细胞靶向

• 批准号: 10535276
• 负责人: Kelly Shea Olsen
• 金额: $ 5.18万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10535276
• 关键词: Acute Myelocytic Leukemia; Alleles; Allogenic; Antigen Targeting; Bioinformatics; Biology; Blood; Bone Marrow; Caring; Caucasians; Cell Line; Cell surface; Cells; Cessation of life; Clinical; Clinical assessments; Data Set; Disease; Disease-Free Survival; Donor person; Ethnic Origin; Ethnic group; Flow Cytometry; Frequencies; Funding; Future; Genetic Polymorphism; Goals; Hematologic Neoplasms; Hematology; Hematopoiesis; Hematopoietic stem cells; Human; I-antigen; Immune system; Immunobiology; Immunologics; Immunology; Immunotherapy; Individual; Knowledge; Leukocytes; Life; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Mediating; Methods; Minor Histocompatibility Antigens; Oncology; Outcome; Patient-Focused Outcomes; Patients; Peptides; Phenotype; Physicians; Population; Population Study; Prevalence; Production; Prognosis; Proteins; Relapse; Research; Role; Sampling; Scientist; Stains; Stem cell transplant; T cell response; T-Lymphocyte; Time; Tissues; Training; Transplant Recipients; Work; acute myeloid leukemia cell; antigen-specific T cells; career; common treatment; curative treatments; cytokine; exhaust; exhaustion; experience; graft vs host disease; graft vs leukemia effect; hematopoietic tissue; improved; large datasets; leukemia; leukemia relapse; leukemia treatment; novel; reconstitution; relapse risk; response; side effect; statistical learning; success; targeted treatment; therapeutic target; tumor immunology

Project Summary/Abstract Acute Myeloid Leukemia (AML) is a prevalent and deadly cancer, with a predicted 20,000 new cases and 11,000 deaths from AML this year in the US. A common treatment for AML is allogeneic stem cell transplantation (alloSCT). Though potentially curative, approximately half of all patients that receive alloSCT eventually relapse and die of their disease. In alloSCT, a patient’s immune system is suppressed and bone marrow hematopoiesis ablated then reconstituted with donor hematopoietic stem cells and leukocytes. Donor T cells are able to recognize peptides derived from recipient genetic polymorphisms as foreign and destroy the cells presenting them. These peptides that differ between donor and recipient are called minor histocompatibility antigens (mHAs). If mHAs are presented on AML cells, donor T cells will kill the AML cells in what is called the graft versus leukemia (GvL) effect. However, donor T cells also target peptides presented on healthy recipient tissues causing a life-threatening side effect called graft versus host disease (GvHD). Separating GvL from GvHD is a pivotal problem in alloSCT biology. T cell targeting of mHAs that are derived from proteins only expressed in the blood is viewed as a way to augment GvL without boosting GvHD. We hypothesize that mHAs mismatched between donor and recipient are a key determinant of alloSCT outcome for AML. In this work, I investigate mHA targeting in alloSCT for AML from two perspectives: mHA and T cell. My work will elucidate the role of mHAs in alloSCT, enrich clinical assessment of AML prognosis, and identify new mHAs for future therapeutic targeting. The training in computational and wet lab immunology included here will forward my goal of becoming an independently funded physician-scientist leading a research lab in leukemia immunobiology and caring for leukemia patients. We have computationally predicted mHAs using a large dataset of over 3000 alloSCT patients. In our mHA- focused Aim 1, I will validate our predicted mHAs using mass spectrometry to identify whether they are presented on the cell surface of AML cell lines and therefore can serve as targets for T cells. Using the mHAs I validate, I will statistically define peptide features that predict presentation on the cell surface by HLA, informing future mHA identification work. I will also assess associations between validated mHAs and clinical outcome after alloSCT. I will analyze mHAs by population frequency in all ethnic groups within the US, with the goal of identifying a minimal set of mHAs that cover the majority of AML patients of all ethnicities. In our T cell-focused Aim 2, we will assess whether T cells specific for mHAs are exhausted in patients experiencing relapse after alloSCT. We predict that efficacy of these T cells predict success of alloSCT, and that exhaustion of these cells will accompany relapse. We will investigate presentation of exhaustion markers and release of proinflammatory cytokines from mHA-specific T cells from alloSCT patients before and after relapse.

项目总结/摘要 急性髓系白血病（AML）是一种流行且致命的癌症，预计20，000例新发病例和11，000例 美国今年的AML死亡人数AML的常见治疗方法是异基因干细胞移植 （alloSCT）。尽管有治愈的潜力，但接受alloSCT的所有患者中约有一半最终复发 死于疾病在alloSCT中，患者的免疫系统受到抑制， 然后用供体造血干细胞和白细胞重建。供体T细胞能够 将来自受体遗传多态性的肽识别为外源肽， 他们这些在供体和受体之间有差异的肽被称为次要组织相容性抗原 （mHAs）。如果mHA存在于AML细胞上，那么供体T细胞将在所谓的移植物抗白血病中杀死AML细胞。 白血病（GvL）效应。然而，供体T细胞也靶向健康受体组织上呈递的肽， 一种称为移植物抗宿主病（GvHD）的危及生命的副作用。将GvL与GvHD分开是一个关键 alloSCT生物学的问题。源自仅在血液中表达的蛋白质的mHA的T细胞靶向 被认为是一种增加GvL而不增加GvHD的方法。我们假设mHA不匹配 供体和受体是AML alloSCT结果的关键决定因素。在这项工作中，我调查mHA的目标 从两个角度：mHA和T细胞。我的工作将阐明mHA在alloSCT中的作用， 丰富AML预后的临床评估，并为未来的治疗靶向确定新的mHA。培训 在计算和湿实验室免疫学包括在这里将推进我的目标，成为一个独立的 他是一位受资助的医生兼科学家，领导着一个白血病免疫生物学研究实验室，并照顾白血病患者。 我们使用超过3000例alloSCT患者的大型数据集计算预测mHA。在我们的mHA- 聚焦目标1，我将使用质谱法验证我们预测的mHA，以确定它们是否存在于 在AML细胞系的细胞表面上，因此可以作为T细胞的靶点。使用我验证的mHA，我 将统计定义预测HLA在细胞表面呈递的肽特征，为未来的mHA提供信息 鉴定工作。我还将评估经验证的mHA与alloSCT后临床结局之间的相关性。 我将分析mHA在美国所有种族群体中的人口频率，目的是确定一个 mHA的最小集合，涵盖所有种族的大多数AML患者。 在我们以T细胞为重点的目标2中，我们将评估患者中mHA特异性T细胞是否耗尽。 alloSCT后复发。我们预测这些T细胞的功效预测alloSCT的成功， 这些细胞的耗尽将伴随复发。我们将研究疲劳标志物的表现， 复发前后alloSCT患者的mHA特异性T细胞释放促炎细胞因子。