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GENETICALLY ENGINEERED T CELLS FOR DIPG

用于 DIPG 的基因工程 T 细胞

基本信息

批准号：
10672286
负责人：
Giedre Krenciute
金额：
$ 50.36万
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：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672286
关键词：
Ablation Address Adoptive Transfer Adult Affect Antigens Antitumor Response Brain Neoplasms CAR T cell therapy CD276 gene CD28 gene CRISPR screen Cancer Etiology Cell Communication Cell Therapy Cell physiology Cell surface Cells Cellular biology Child Childhood Brain Neoplasm Clinical Clinical Research Data Development Diffuse intrinsic pontine glioma Disease model Endoplasmic Reticulum Engineering Evaluation Flow Cytometry Frequencies GRP78 gene Gene Deletion Genes Genetic Engineering Goals Golgi Apparatus Human Immune Immune response Immunocompetent Immunologic Deficiency Syndromes Immunooncology Immunotherapy In Vitro Intervention Intrinsic factor Knock-out Knowledge Learning Literature Macrophage Mediating Methods Modeling Molecular Molecular Target Mouse Strains Mus Myeloid Cells Outcome Pathway interactions Patients Phase Phenotype Population Proteins Publishing Role Safety Signal Pathway Solid Neoplasm Subgroup Surface T-Cell Activation T-Cell Receptor T-Lymphocyte TNFRSF5 gene Testing Translations Tumor Antigens Xenograft Model antigen-specific T cells cancer cell childhood cancer mortality chimeric antigen receptor chimeric antigen receptor T cells clinically relevant cytokine design diffuse midline glioma effective therapy effector T cell efficacy evaluation endoplasmic reticulum stress engineered T cells eosinophil exhaustion experience genome wide screen genome-wide glioma cell line glucose-regulated proteins human disease immune cell infiltrate improved improved outcome in vitro activity in vivo innovative technologies monocyte mouse model multidisciplinary neoplastic cell novel novel therapeutics pediatric patients pre-clinical prototype response safety testing tool tumor tumor heterogeneity tumor-immune system interactions

项目摘要

PROJECT ABSTRACT Genetically engineered T cells for DIPG The overall objective of this study is to engineer an effective and safe chimeric antigen receptor (CAR) T-cell therapy for diffuse intrinsic pontine glioma (DIPG), a subgroup of diffuse midline gliomas for which currently there is no cure. CAR T-cell therapy is an innovative technology based on adoptive transfer of antigen-specific T cells engineered to elicit a clinically effective and specific immune response against tumor cells. Early clinical studies in adult patients demonstrated the safety of CAR T-cell therapy for brain tumors, yet found only limited benefits. This lack of efficacy is most likely multifactorial and includes T-cell exhaustion, the immunosuppressive tumor microenvironment, and the paucity of brain tumor-specific antigens. Thus, we propose to develop CAR T cells targeting glucose-regulated protein 78 (GRP78), a novel DIPG-specific antigen. To further improve the effector function of GRP78-CAR T cells, we also propose to target a novel negative T-cell regulator called RASA2. We hypothesize that CAR T cells targeting GRP78 on the surface of tumor cells and lacking RASA2 can be developed as a safe, effective treatment for DIPGs and that evaluation of this intervention in DIPG mouse models that closely mimic human disease will identify T-cell extrinsic negative regulators of CAR T-cell function. Here we propose 3 interrelated Specific Aims to test this hypothesis. The rationale of each Aim is outlined below. In Aim 1, we will first target GRP78 and optimize the CAR design. To that end, we will generate CARs containing different co-stimulatory domains (41BB.ζ, MyD88.ζ, or MyD88.CD40.ζ) and compare their activity in vitro. Then we will evaluate the efficacy and safety of the active CAR(s) in vivo by using immunodeficient and immunocompetent mouse models of DIPG. A genome-wide screen in primary T cells has identified key regulators of T-cell activation after T-cell receptor stimulation. One of the identified genes, RASA2, has not been studied in T cells. In Aim 2, we will elucidate the mechanism by which the deletion of RASA2 enhances the effector function of CAR T cells and then delete the gene from GRP78-CAR T cells to enhance their function. Finally, in Aim 3, we will characterize the components of the DIPG microenvironment and examine the interactions between endogenous DIPG immune cells and CAR T–cell treatment. State-of-the-art methods will be used in all 3 Aims to study not only the function and in vivo fate of CAR T cells but also their antitumor activity and how they interact with DIPG-infiltrating immune cells (i.e., macrophages, eosinophils, monocytes). Our preliminary studies indicate that prototype GRP78-CAR T cells readily recognize and kill DIPG cells in vitro and have antitumor activity against solid tumors in vivo, highlighting that the developed models are well suited for the proposed Aims. To support the rapid translation of findings from this project to the clinical setting, we will use multiple DIPG mouse models that closely recapitulate human disease. Upon completion of this study, we will have defined the optimal GRP78-CAR design that safely eliminates DIPG tumors and persists long term in the DIPG immune microenvironment.

项目摘要