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.

项目概要 该提案的重点是在临床前胶质母细胞瘤 (GBM) 中使用 T 细胞受体 (TCR) 定向治疗 GBM 仍然是一种难以治疗的癌症，尽管如此，临床结果仍然很差。 尽管免疫疗法对癌症产生巨大影响，但目前 FDA 尚未批准针对 GBM 的免疫疗法。 将基于免疫的治疗扩展到中枢的困难有几个原因 GBM 中的神经系统 (CNS) 含有很少的 T 细胞，被认为是“非炎症”的，因此很少有 T 细胞。 脑实质中的树突状细胞，并且已在 由于存在未见的位点特异性元件，中枢神经系统也具有免疫学特化。 其他地方——例如，缺乏淋巴结、存在硬脑膜淋巴管和血脑屏障等 此外，GBM 的基因组景观在许多抗原和基因方面引入了额外的障碍。 重要的是，新抗原靶标的分布是异质的，尽管异质性是一个巨大的问题。 尽管存在这些障碍，但免疫疗法在临床前环境中的建模却很差。 CNS 免疫疗法的最终目标——T 细胞克隆扩增——保持不变。在这里，我们将测试其用途。 过继转移 TCR 定向 T 细胞治疗临床前 GBM，作为了解关键的门户 我们与 Charest 博士和 Dr. Charest 组建了一个团队。 佩蒂为这项工作带来了不同的专业知识，拟议的工作重点是一种新型转基因小鼠。 在 GL261 小鼠模型中，靶向内源性新抗原突变体 Imp3 (mImp3)。 突变型 Imp3 特异性转基因 (MISTIC) 小鼠，表达可识别 H2-Db 限制性蛋白的 TCR mImp3 新抗原因此代表了 TCR 定向细胞治疗的令人兴奋的模型。在目标 1 中，我们将。 剖析 MISTIC 治疗的机制，并了解内源性的需求 RAG 依赖性淋巴细胞群的有效治疗此外，我们将开发和研究一种新的、 自发的、EGFR 驱动的和新抗原定义的 GBM 模型的本土模型，使我们能够 在生理环境中研究 MISTIC 细胞疗法 在目标 2 中，我们将研究一小部分的观察结果。 小鼠逃避 MISTIC 治疗，并通过询问分子和细胞因子在延长生存期后取得进展 在目标 3 中，通过表征肿瘤和微环境的变化来确定耐药性。 我们将使用我们的等基因、CRISPR 编辑的 GL261 克隆和野生型 Imp3 来模拟异质性并探索 使用细胞因子和趋化因子改造 MISTIC 细胞，旨在重塑 GBM 我们将这种方法视为一种证明——微环境。 使用单抗原系统释放表位扩散的概念一起，这些目标将揭示新的目标。 TCR 细胞治疗模型的见解将导致新型本土模型的开发和探索 GBM 异质性的工程方法一起具有直接的转化应用。