Engineering T Cell Adoptive Therapy for Glioblastoma

胶质母细胞瘤的工程 T 细胞过继疗法

• 批准号: 10752995
• 负责人: Alain Charest
• 金额: $ 65.84万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752995
• 关键词: Address; Adoptive Cell Transfers; Adoptive Transfer; Adult; Aftercare; Anatomy; Antigen Presentation; Antigen Targeting; Antigens; Biological; Biological Models; Blood - brain barrier anatomy; Brain Neoplasms; Cell Therapy; Cells; Central Nervous System; Central Nervous System Diseases; Clinical; Clonal Expansion; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Dendritic Cells; Diagnosis; Disease; Elements; Engineering; Epidermal Growth Factor Receptor; Epitope spreading; Escape Mutant; FDA approved; Foundations; Functional disorder; Genomics; Glioblastoma; Goals; Growth Factor; Heterogeneity; Immunobiology; Immunologics; Immunotherapeutic agent; Immunotherapy; Infiltration; Location; Lymphatic; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of central nervous system; Modeling; Molecular; Mus; Myelogenous; Nature; Neoplasm Transplantation; Observational Study; Oncology; Outcome; Pathway interactions; Patients; Physiological; Population; Process; Resistance; Resolution; Site; System; T cell infiltration; T cell response; T cell therapy; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; Transplantation; Treatment Efficacy; Tumor Antigens; Tumor Escape; Work; aggressive therapy; antigen-specific T cells; brain parenchyma; cancer immunotherapy; cellular engineering; chemokine; clinical translation; cytokine; design; effective therapy; efficacy testing; engineered T cells; epigenomics; gene therapy; immunogenic; immunogenicity; improved; inhibitor; insight; lymph nodes; model development; mouse model; mutant; neoantigens; neoplastic cell; novel; pre-clinical; targeted treatment; therapy development; transcriptomics; translational applications; tumor; tumor heterogeneity; tumor progression

PROJECT SUMMARY This proposal centers on the use of T cell receptor (TCR) directed therapy in preclinical glioblastoma (GBM) models. GBM remains a difficult cancer to treat, and clinical outcomes remain poor. However, despite the seismic influence of immunotherapy in cancer, there remain no FDA approved immunotherapies for GBM. There are several reasons that underlie the difficulty in extending immune-based treatments to the central nervous system (CNS). GBM harbors few T cells and is considered “non-inflamed”, there is a paucity of dendritic cells in the brain parenchyma, and a myriad of immunosuppressive features has been identified in patients. The CNS is also immunologically specialized due to the presence of site-specific elements not seen elsewhere—e.g., lack of lymph nodes, presence of dural lymphatics, and the blood-brain barrier, among others. Moreover, the genomic landscape of GBM introduces additional obstacles in that many antigenic and neoantigenic targets are heterogeneously distributed. Importantly, although heterogeneity is a formidable challenge to immunotherapy, it is poorly modeled in preclinical settings. Despite these barriers, however, the final goal of CNS immunotherapy—T cell clonal expansion—remains the same. Here, we will test the use of adoptively transferred TCR directed T cells to treat preclinical GBM as a gateway to understand key mechanistic principles for ultimate clinical translation. We have assembled a team with Dr. Charest and Dr. Petti that brings diverse expertise to this work. The proposed work focuses on a novel transgenic mouse that targets an endogenous neoantigen, mutant Imp3 (mImp3), in the GL261 mouse model. This mouse, the Mutant Imp3 Specific TransgenIC (MISTIC) mouse, expresses a TCR that recognizes the H2-Db restricted mImp3 neoantigen and thus represents an exciting model for TCR-directed cell therapy. In Aim 1, we will dissect the mechanisms underlying MISTIC therapy and also understand the requirement for endogenous RAG-dependent lymphocyte populations in effective treatment. Additionally, we will develop and study a new, autochthonous model of spontaneous, EGFR-driven and neoantigenically-defined GBM model to allow us to study MISTIC cell therapy in physiologic settings. In Aim 2, we will study the observation that a small subset of mice escape MISTIC therapy and progress after prolonged survival by interrogating the molecular and cellular basis of resistance by characterizing changes at both the level of the tumor and microenvironment. In Aim 3, we will use our isogenic, CRISPR-edited GL261 clones with wild type Imp3 to model heterogeneity and explore the engineering of MISTIC cells with cytokines and chemokines designed to remodel the GBM microenvironment as a platform to target heterogeneous tumors. We envision this approach as a proof-of - concept to use single-antigen systems to unleash epitope spreading. Together, these Aims will reveal new insights from a TCR cell therapy model that will lead to novel autochthonous model development and explore engineering approaches for GBM heterogeneity that, together, have immediate translational applications.

项目摘要 该建议集中于在临床前胶质母细胞瘤（GBM）中使用T细胞受体（TCR）的治疗 型号。 GBM仍然很难治疗，临床结果仍然很差。但是，要求 免疫疗法在癌症中的抗震影响，FDA尚无批准的GBM免疫疗法。 有几个原因是将免疫治疗扩展到中央的困难是很难的 神经系统（CNS）。 GBM拥有很少的T细胞，被认为是“非侵蚀”，很少 在脑实质中的树突状细胞和无数的免疫抑制特征已在 患者。由于未见地点特异性元素的存在，中枢神经系统也具有免疫学专业化 在其他地方 - 例如，缺乏淋巴结，存在硬脑膜淋巴染和血脑屏障， 其他的。此外，GBM的基因组景观在许多抗原和 新抗原靶标是异质分布的。重要的是，尽管异质性是强大的 对免疫疗法的挑战，它在临床前环境中的建模很差。尽管有这些障碍，但是 CNS免疫疗法的最终目标（细胞克隆扩张）也是如此。在这里，我们将测试 采用的TCR定向T细胞将临床前GBM视为了解钥匙的门户 最终临床翻译的机械原理。我们已经与Charest博士和Dr. Petti为这项工作带来了多种专业知识。拟议的工作重点是一种新型的转基因小鼠 在GL261小鼠模型中靶向内源性新抗原突变体IMP3（MIMP3）。这只鼠标， 突变的IMP3特异性转基因（Mistic）小鼠，表达识别受H2-DB受限的TCR MIMP3新抗原，因此代表了TCR指导细胞疗法的令人兴奋的模型。在AIM 1中，我们将 剖析模拟疗法的基础机制，也了解内源性的要求 在有效治疗中，依赖RAG的淋巴细胞群体。此外，我们将开发和研究一个新的 赞助商，EGFR驱动和新抗原定义的GBM模型的自我围门模型，使我们能够 在生理环境中研究模拟细胞疗法。在AIM 2中，我们将研究以下观察 小鼠通过询问分子和细胞来避免了模拟疗法和长期生存后的进展 通过表征肿瘤和微环境水平的变化来表征抗性的基础。在AIM 3中， 我们将使用带有野生型IMP3的等源性，CRISPR编辑的GL261克隆来建模异质性并探索 用细胞因子和趋化因子的工程设计，旨在重塑GBM 微环境是针对异质肿瘤的平台。我们将这种方法视为一种证明 - 使用单抗原系统释放发作的概念。这些目标在一起将揭示新的 TCR细胞疗法模型的见解，该模型将导致新型的自动模型开发并探索 GBM异质性的工程方法共同具有直接的翻译应用。