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Improving genetically engineered T cells for medulloblastomas

改善髓母细胞瘤基因工程 T 细胞

基本信息

批准号：
10390362
负责人：
Giedre Krenciute
金额：
$ 44.48万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10390362
关键词：
Ablation Address Antigens Antitumor Response B lymphoid malignancy Brain Neoplasms CD276 gene CSF1R gene Cancerous Cell Therapy Cell physiology Cells Child Childhood Brain Neoplasm Childhood Malignant Brain Tumor Clinical Research Combined Modality Therapy Cytosine DNA DNA Modification Methylases Dioxygenases ERBB2 gene Engineered Gene Engineering Epigenetic Process Frequencies Future Genetic Genetic Engineering Health Immune Immune response Immune system Immunocompetent Immunotherapy Infusion procedures Innovative Therapy Institution Knowledge Lead Left Macrophage Colony-Stimulating Factor Malignant Neoplasms Mediating Mediator of activation protein Methods Methyltransferase Modification Molecular Mus Neoplasm Metastasis Patients Performance Phase I Clinical Trials Pre-Clinical Model Production Relapse Resistance Resources Signal Transduction Specificity T-Cell Immunologic Specificity T-Lymphocyte Testing Tetanus Helper Peptide Text Therapeutic Tissues Tumor Antigens Tumor-associated macrophages Xenograft procedure angiogenesis antigen challenge antigen-specific T cells antitumor effect base cancer cell cancer therapy chimeric antigen receptor chimeric antigen receptor T cells conventional therapy cytokine effector T cell engineered T cells exhaustion experience experimental study immunoengineering improved improved outcome inhibitor insight leukemia medulloblastoma mouse model negative affect novel therapeutic intervention pre-clinical preclinical study programs receptor recruit safety engineering side effect success tool tumor tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

Title: Improving genetically engineered T cells for medulloblastoma PROJECT SUMMARY/ABSTRACT The intent of this project is to develop antigen-specific T cells as an effective immunotherapy for medulloblastoma (MB), a most common pediatric brain tumor. While recent advances in MB treatment slightly improved the overall survival, the patients are left with long-term devastating side effects as a result of a treatment. The body’s natural immune defenses against cancer often fail because the cancer either does not provoke or actively inhibits immune responses. However, genetic modification of the patient’s own immune system can be used to endow T cells with improved ability to recognize and kill cancerous cells that would not otherwise respond to conventional therapies. Cancer treatments consisting of the infusion of T cells that are engineered to recognize tumor antigens, molecules present only on cancers cells, have shown dramatic success in clinical studies against leukemia. We now propose to develop such approach for MB. In our method, we will target two antigens called IL13Ra2 and B7-H3 which are present on MB cells. Next, we will improve our approach by deleting epigenetic regulators that are known to suppress T cell effector function. Finally, we will use an immunocompetent MB mouse model to ask which immune cells within brain tumor microenvironment (TME) control CAR T cell efficacy. Brain tumors are notorious for having an immunosuppressive TME, yet its effect on engineered immune cells are poorly understood. Thus, the use of mouse models with functional immune system will allow us to accurately evaluate the function and safety of engineered T cells as well as understand the brain TME. In summary, we propose to first establish CAR T cells targeting two antigens in order to improve their specificity (Aim 1). We will then improve their persistence through ablation of epigenetic programs (Aim 2). We will also perform a detailed mechanistic study to determine how epigenetic regulators control effector function of engineered CAR T cells. Finally, we will investigate if elimination of key inhibitory immune cells within the brain TME will enhance anti- tumor effects of CAR T cells (Aim 3). We expect that our proposed studies using gene engineered bi-specific CAR T cells and immunocompetent mouse model will provide mechanistic insight and superior understanding on how engineered T cells function and interact with the brain TME. We believe that such knowledge will lead not only to the creation of improved immune cell-based approaches but also to potential novel therapeutic approaches for brain tumors in the future. If our pre-clinical approach is successful, we have the resources to develop a Phase I clinical trial at our institution.

题目：改良基因工程T细胞治疗成神经管细胞瘤