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：
10581552
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/10581552
关键词：
Ablation Address Antigens Antitumor Response B lymphoid malignancy Brain Neoplasms CD276 gene CSF1R gene Cancerous Cell Communication Cell Therapy Cell physiology Cells Child Childhood Brain Neoplasm Childhood Malignant Brain Tumor Clinical Research Combined Modality Therapy DNA DNA Modification Methylases Dioxygenases ERBB2 gene Endowment Engineered Gene Engineering Epigenetic Process Frequencies Future Genetic Genetic Engineering Health IL13RA1 gene Immune Immune response Immune system Immunocompetent Immunotherapy Infusion procedures Innovative Therapy Institution Knowledge Lead Left Macrophage Colony-Stimulating Factor Malignant Neoplasms Mediating Mediator Methods Methyltransferase Modification Molecular Mus Neoplasm Metastasis Patients Performance Phase I Clinical Trials Pre-Clinical Model Production Recurrence Recurrent tumor Relapse Resistance Resources Signal Transduction Specificity T-Cell Immunologic Specificity T-Lymphocyte Testing Tetanus Helper Peptide Text Therapeutic Tissues Tumor Antigens Tumor Promotion Tumor-associated macrophages Xenograft procedure angiogenesis antigen challenge antigen-specific T cells antitumor effect 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 synergism 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.

标题：改善髓母细胞瘤基因工程 T 细胞项目概要/摘要该项目的目的是开发抗原特异性 T 细胞作为髓母细胞瘤的有效免疫疗法 (MB)，一种最常见的儿童脑肿瘤，而 MB 治疗的最新进展略有改善。为了生存，患者会因治疗而留下长期的破坏性副作用。针对癌症的免疫防御常常失败，因为癌症要么不引发，要么主动抑制然而，可以利用患者自身免疫系统的基因改造来赋予免疫反应。 T 细胞具有更高的识别和杀死癌细胞的能力，否则这些癌细胞不会产生反应传统疗法包括输注经过改造的可识别 T 细胞。肿瘤抗原是仅存在于癌细胞上的分子，在针对癌症的临床研究中已显示出巨大的成功我们现在建议开发这种针对 MB 的方法，我们将针对两种称为 MB 的抗原。接下来，我们将通过删除表观遗传来改进我们的方法。最后，我们将使用具有免疫功能的 MB。小鼠模型询问脑肿瘤微环境 (TME) 中哪些免疫细胞控制 CAR T 细胞功效。脑肿瘤因具有免疫抑制性 TME 而臭名昭著，但它对工程免疫细胞的影响因此，使用具有功能性免疫系统的小鼠模型将使我们能够准确地了解。评估工程 T 细胞的功能和安全性以及了解大脑 TME 总而言之，我们。我们将首先提出建立针对两种抗原的CAR T细胞，以提高其特异性（目标1）。然后通过消除表观遗传程序来提高它们的持久性（目标 2）。机制研究以确定表观遗传调节剂如何控制工程化 CAR T 细胞的效应功能。最后，我们将研究消除大脑 TME 内的关键抑制性免疫细胞是否会增强抗- CAR T 细胞的肿瘤效应（目标 3）我们期望我们提出的研究使用基因工程双特异性。 CAR T 细胞和免疫活性小鼠模型将提供机制洞察和高级理解关于工程 T 细胞如何发挥作用并与大脑 TME 相互作用，我们相信这些知识将引领我们的发展。不仅是为了创建改进的基于免疫细胞的方法，而且是为了潜在的治疗新方法如果我们的临床前方法成功，我们就有资源来治疗脑肿瘤。在我们的机构开展 I 期临床试验。