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/文摘