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

基本信息

批准号：
10689701
负责人：
Kelly Shea Olsen
金额：
$ 5.27万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
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/10689701
关键词：
Ablation Acute Myelocytic Leukemia Alleles Allogenic Antigen Presentation 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 Population Flow Cytometry Frequencies Funding Future Genetic Polymorphism Goals Hematologic Neoplasms Hematology Hematopoiesis Hematopoietic stem cells Human Immune system Immunobiology Immunologics Immunology Immunotherapy Individual Inflammatory 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 novel reconstitution relapse risk response side effect statistical learning success targeted treatment therapeutic target tumor immunology

项目摘要

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.

项目概要/摘要急性髓系白血病 (AML) 是一种流行且致命的癌症，预计有 20,000 例新病例和 11,000 例今年美国有 1 例 AML 死亡病例，一种常见的 AML 治疗方法是同种异体干细胞移植。（alloSCT）虽然有可能治愈，但接受 alloSCT 的所有患者中约有一半最终会复发。在同种异体干细胞移植中，患者的免疫系统和骨髓造血受到抑制。消融然后用供体造血干细胞和供体 T 细胞重建。将源自受体遗传多态性的肽识别为外来肽并破坏呈递的细胞这些在供体和受体之间存在差异的肽被称为次要组织相容性抗原。 (mHA) 如果 mHA 出现在 AML 细胞上，供体 T 细胞将在所谓的移植物对抗中杀死 AML 细胞。然而，供体 T 细胞也会靶向健康受体组织上存在的肽，从而导致白血病 (GvL) 效应。一种称为移植物抗宿主病 (GvHD) 的危及生命的副作用是区分 GvL 和 GvHD 的关键。 alloSCT 生物学中的 T 细胞靶向源自仅在血液中表达的蛋白质的 mHA 的问题。被视为一种增强 GvL 而不增强 GvHD 的方法，我们发现 mHA 之间不匹配。供体和受体是 AML 的 alloSCT 结果的关键决定因素。在这项工作中，我研究了 mHA 靶向。我的工作将从两个角度阐述 mHA 在 alloSCT 中对 AML 的作用：mHA 和 T 细胞。丰富 AML 预后的临床评估，并确定新的 mHA 以用于未来的治疗靶向培训。这里包含的计算和湿实验室免疫学将推动我成为独立的目标资助的医师科学家领导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 名 alloSCT 患者的大型数据集通过计算预测了 mHA。重点目标 1，我将使用质谱验证我们预测的 mHA，以确定它们是否存在位于 AML 细胞系的细胞表面，因此可以作为 T 细胞的靶标。将具体定义预测 HLA 在细胞表面呈现的肽特征，为未来的 mHA 提供信息我还将评估经过验证的 mHA 与 alloSCT 后临床结果之间的关联。我将根据美国境内所有种族群体的人口频率来分析 mHA，目的是确定一个覆盖所有种族的大多数 AML 患者的最小 mHA 集。在我们以 T 细胞为重点的目标 2 中，我们将评估患者体内 mHA 特异性 T 细胞是否耗尽 alloSCT 后出现复发，我们预测这些 T 细胞的功效预示着 alloSCT 的成功。这些细胞的耗竭将伴随着复发。我们将研究耗竭标志物的呈现和情况。 alloSCT 患者复发前后 mHA 特异性 T 细胞释放促炎细胞因子。