Improving genetically engineered T cells for medulloblastomas

改善髓母细胞瘤基因工程 T 细胞

• 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
• 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

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：改善基因工程T细胞治疗髓母细胞瘤 项目总结/摘要 本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)是最常见的小儿脑肿瘤。虽然MB治疗的最新进展略微改善了整体 为了生存，患者会因治疗而留下长期的破坏性副作用。身体的自然 对癌症的免疫防御经常失败，因为癌症要么不激发，要么主动抑制， 免疫反应。然而，对患者自身免疫系统的基因改造可以用来赋予 T细胞识别和杀死癌细胞的能力提高，否则这些癌细胞不会对免疫应答。 传统疗法。癌症治疗包括输注T细胞，这些T细胞被设计为识别 肿瘤抗原，仅存在于癌细胞上的分子，在临床研究中显示出巨大的成功， 白血病我们现在建议为MB开发这种方法。在我们的方法中，我们将靶向两种抗原， IL 13 Ra 2和B7-H3，其存在于MB细胞上。接下来，我们将通过删除表观遗传来改进我们的方法。 已知抑制T细胞效应子功能的调节子。最后，我们将使用免疫活性MB 小鼠模型，以询问脑肿瘤微环境（TME）中的哪些免疫细胞控制CAR T细胞功效。 脑肿瘤因具有免疫抑制性TME而臭名昭著，但其对工程免疫细胞的影响 我们对此知之甚少。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 评估工程化T细胞的功能和安全性，并了解大脑TME。总之，我们 提出首先建立靶向两种抗原的CAR T细胞，以提高其特异性（目标1）。我们将 然后通过消除表观遗传程序来提高其持久性（目标2）。我们还将进行详细的 这是一项机制研究，以确定表观遗传调节剂如何控制工程化CAR T细胞的效应子功能。 最后，我们将研究消除脑TME内的关键抑制性免疫细胞是否会增强抗TME的作用。 CAR T细胞的肿瘤效应（Aim 3）。我们希望我们提出的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上级理解 关于工程化T细胞如何发挥作用并与大脑TME相互作用。我们相信，这些知识将导致 这不仅有助于建立改进的基于免疫细胞的方法， 脑肿瘤的治疗方法。如果我们的临床前方法成功，我们就有资源 在我们的机构开展I期临床试验。