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Synergistic microglial activation and tumor cell killing for improved GBM response

协同小胶质细胞激活和肿瘤细胞杀伤可改善 GBM 反应

基本信息

批准号：
10328499
负责人：
Vidyalakshmi Chandramohan
金额：
$ 40.25万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-15 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10328499
关键词：
Ablation Abscopal effect Adult Affinity Animal Model Animals Antigen Presentation Antigen-Presenting Cells Antigens Antitumor Response Automobile Driving Binding Brain Brain Neoplasms CD8-Positive T-Lymphocytes CD8B1 gene Cells Clinic Clinical Combined Modality Therapy Contralateral Cytotoxic Chemotherapy Development Disease Education Effectiveness Epidermal Growth Factor Receptor Generations Glioblastoma Glioma Goals ITGAX gene Immune Immunocompetent Immunoglobulin Fragments Immunosuppression Immunotoxin Therapy Immunotoxins In Vitro Individual Inflammatory Infusion procedures Ipsilateral Ligation Malignant neoplasm of brain Mediating Mediator of activation protein Microglia Modeling Molecular Multiple Sclerosis Mus Oncogenes Outcome Patients Phagocytosis Phase I Clinical Trials Phenotype Primary Brain Neoplasms Radiology Specialty Recombinant Antibody Recurrence Research Role T cell response T-Cell Activation T-Lymphocyte TNFRSF5 gene Testing Therapeutic Translating Tumor Antigens Tumor Immunity Tumor-associated macrophages Tumor-infiltrating immune cells Variant anti-tumor immune response base cell growth cell killing clinical translation cytotoxic cytotoxic CD8 T cells defined contribution effective therapy effector T cell improved in vivo innovation insight macrophage mortality mutant neoplastic cell novel novel strategies novel therapeutic intervention novel therapeutics patient response patient subsets pre-clinical preclinical study public health relevance radiological imaging response subcutaneous survival outcome transcriptome transcriptomics tumor tumor microenvironment tumor-immune system interactions

项目摘要

PROJECT SUMMARY/ABSTRACT Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Current therapies remain unsuccessful in improving overall survival; thus, the identification of novel therapies for GBM is critical. We have pioneered a novel, targeted immunotoxin (IT)-based cytotoxic therapy, D2C7-IT, that targets epidermal growth factor receptor (EGFR) and mutant EGFR variant III (EGFRvIII), established driver oncogenes of GBM. In preclinical studies, D2C7-IT targets and kills a substantial number of tumor cells and prolongs survival but is unable to generate cures in all treated animals because of the presence of a highly immunosuppressive GBM microenvironment. The majority of the immune cells in the GBM microenvironment are tumor-associated macrophages (TAMs), which promote tumor cell growth and inhibit antitumor T cell responses. Therefore, eliminating TAM-mediated immunosuppression is anticipated to enhance D2C7-IT-induced antitumor immune responses. CD40 is an immune co-stimulatory molecule whose activation is known to re-educate TAMs, and also induce T cell responses. Thus, the central hypothesis driving the present proposal is that overcoming TAM immunosuppression and tumor-promoting activities via CD40 co-stimulation will improve the efficacy of the cytotoxic D2C7-IT therapy. Accordingly, our preliminary studies have demonstrated that (1) in a mouse glioma model, D2C7-IT+αCD40 functions synergistically to prolong survival and generate significant cures, (2) brain resident microglia is the principal antigen-presenting cells (APCs) activated by the combination therapy, and (3) αCD40 treatment engages CD8+ effector T cells that are antitumorigenic only when combined with cytotoxic D2C7-IT. Our results strongly imply that αCD40 alters either the development or activity of TAMs in GBM and activates microglia/T cells. Demonstrating the antitumor efficacy of the D2C7-IT+αCD40 therapy in relevant brain tumor models and gaining insights into their mechanism of action will greatly aid in the clinical translation of D2C7-IT+αCD40 therapy. Therefore, we propose to pursue three Specific Aims to characterize D2C7-IT+αCD40 antitumor efficacy, TAM re-education, and microglia/T cell activation mechanisms: Aim 1: Evaluate whether αCD40 overcomes TAM immunosuppression and enhances D2C7-IT efficacy in two preclinical immunocompetent glioma models. Aim 2: Define whether microglial CD40/MHCII molecules are the mediators of D2C7-IT+αCD40 antitumor immune response. Aim 3: Determine whether D2C7-IT+αCD40 therapy stimulates CD8+ effector T cell response capable of eliminating antigen-positive as well as antigen-negative tumors. The proposed research is significant because it will result in the development of a therapeutic strategy for simultaneous tumor cell killing, reversal of TAM immunosuppression, activation of microglia and T cells, and ultimately could be translated and tested in the clinic.

项目总结/文摘