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: 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
• 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

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.

项目摘要/摘要 急性髓样白血病（AML）是一种普遍且致命的癌症，预计有20,000例新病例和11,000例 今年在美国的AML死亡。 AML的常见治疗方法是同种异体干细胞移植 （Allosct）。尽管有潜在的治疗方法，但大约有一半接受同种的患者最终中继 并死于他们的疾病。在Allosct中，患者的免疫系统被抑制和骨髓造血 然后用供体造血干细胞和白细胞重构。供体T细胞能够 源自受体遗传多态性的识别肽作为异物并破坏了呈现的细胞 他们。这些供体和受体不同的肽称为较小的组织相容性抗原 （MHA）。如果在AML细胞上呈现MHA，则供体T细胞将杀死AML细胞，而所谓的移植物与 白血病（GVL）效应。但是，供体T细胞还靶向在健康受体组织上呈现的肽 威胁生命的副作用称为移植物与宿主疾病（GVHD）。将GVL与GVHD分开是关键 Allosct生物学中的问题。 T细胞的靶向MHA的靶标，这些蛋白仅在血液中表达 被视为不增加GVHD的增强GVL的一种方式。我们假设MHA之间的MHA不匹配 捐助者和收件人是AML同种结果结果的关键确定剂。在这项工作中，我调查了MHA的目标 从两个角度来看AML的Allosct：MHA和T细胞。我的工作将阐明MHA在Allosct中的作用， 丰富对AML预后的临床评估，并确定未来治疗靶向的新MHA。培训 在此处包括的计算和湿实验室免疫学中，我的目标是成为独立的目标 资助的身体科学家领导了白血病免疫生物学研究实验室，并照顾白血病患者。 我们使用了3000多名AlloSCT患者的大型数据集进行了计算预测的MHA。在我们的MHA- 集中目的1，我将使用质谱法验证我们的预测MHA，以确定它们是否呈现 在AML细胞系的细胞表面上，因此可以用作T细胞的靶标。使用我验证的MHA，我 将从统计上定义肽特征，这些特征可以通过HLA预测细胞表面的呈现，并告知未来的MHA 身份证工作。我还将评估AlloSCT后验证的MHA和临床结果之间的关联。 我将根据美国境内所有种族的人口频率分析MHA，目的是确定 覆盖大多数种族的大多数AML患者的MHA最少。 在我们以T细胞为重点的AIM 2中，我们将评估患者特异性的T细胞是否耗尽 在同and后体验继电器。我们预测，这些T细胞的有效性预测了同种特性的成功，并且 这些细胞的耗尽将参与继电器。我们将调查耗尽标记的呈现和 释放前后，来自同种症患者的MHA特异性T细胞的促炎细胞因子释放。