Improving genetically engineered T cells for medulloblastomas

标题：改良基因工程T细胞治疗髓母细胞瘤 项目摘要/摘要 这个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。虽然最近在甲基溴治疗方面的进展略有改善，但总体上 存活下来，患者会因为治疗而留下长期破坏性的副作用。身体是天然的 对癌症的免疫防御常常失败，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 识别和杀死癌细胞的能力得到改善的T细胞，否则这些癌细胞不会有反应 传统疗法。癌症治疗包括输注T细胞，这些T细胞被设计成识别 肿瘤抗原是只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。我们现在提议为甲基溴制定这样的办法。在我们的方法中，我们将针对两种抗原，称为 存在于MB细胞上的IL13RA2和B7-H3。接下来，我们将通过删除表观遗传学来改进我们的方法 已知的抑制T细胞效应器功能的调节剂。最后，我们将使用具有免疫活性的MB 以小鼠为模型，询问脑肿瘤微环境(TME)内哪些免疫细胞控制CAR T细胞的疗效。 脑瘤以具有免疫抑制作用而臭名昭著，但它对工程免疫细胞的影响 人们对此了解甚少。因此，使用具有功能免疫系统的小鼠模型将使我们能够准确地 评估工程T细胞的功能和安全性，以及了解大脑的TME。总而言之，我们 建议首先建立针对两种抗原的CAR T细胞，以提高其特异性(目标1)。我们会 然后通过消融表观遗传程序来提高它们的持久性(目标2)。我们还将执行一项详细的 确定表观遗传调节因子如何控制工程CAR T细胞的效应功能的机制研究。 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)。我们希望我们提出的使用基因工程双特异性的研究 CAR T细胞和免疫活性小鼠模型将提供机械洞察力和卓越的理解 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，这样的知识将导致 不仅有助于创造改进的基于免疫细胞的方法，而且还有助于潜在的新疗法 未来脑瘤的治疗方法。如果我们的临床前方法成功，我们有足够的资源 在我们机构进行I期临床试验。

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.