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：
10092562
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/10092562
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 Diagnostic radiologic examination 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 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.

项目摘要/摘要胶质母细胞瘤（GBM）是成年人中最常见，最具侵略性的原发性脑肿瘤。当前的疗法仍然存在改善总体生存期的不成功；因此，GBM的新疗法的鉴定至关重要。我们有开创了一种基于新型的，有针对性的免疫毒素（IT）的细胞毒性疗法D2C7-IT，该治疗靶向表皮生长因子受体（EGFR）和突变体EGFR变体III（EGFRVIII），已建立的GBM的驱动器发育不全。在临床前研究，D2C7-IT目标并杀死大量肿瘤细胞并延长生存率，但IS 由于存在高度免疫抑制GBM，因此无法在所有处理过的动物中产生疗法微环境。 GBM微环境中的大多数免疫细胞是肿瘤相关的巨噬细胞（TAM），促进肿瘤细胞生长并抑制抗肿瘤T细胞反应。所以，预计消除TAM介导的免疫抑制会增强D2C7-IT诱导的抗肿瘤免疫回答。 CD40是一种免疫刺激性分子，已知活化会重新教育TAM，并且还诱导T细胞反应。那是推动当前建议的中心假设是克服通过CD40共刺激TAM免疫抑制和促进肿瘤活性将改善细胞毒性D2C7-IT治疗的功效。根据，我们的初步研究表明（1）小鼠胶质瘤模型，D2C7-IT+αCD40协同起作用可延长生存率并产生重要的生存率（2）脑居民小胶质细胞是由组合激活的主要抗原细胞（APC）治疗，（3）αCD40治疗仅在合并时抗肿瘤的CD8+效应T细胞与细胞毒性D2C7-IT。我们的结果强烈暗示αCD40改变了TAM的发展或活性在GBM中并激活小胶质细胞/T细胞。证明D2C7-IT+αCD40治疗的抗肿瘤效率相关的脑肿瘤模型并获得对其作用机制的见解将极大地有助于临床 D2C7-IT+αCD40治疗的翻译。因此，我们建议追求三个特定目标以表征 D2C7-IT+αCD40抗肿瘤效率，TAM重新教育和小胶质细胞/T细胞激活机制：AIM 1：评估αCD40是否克服了TAM免疫抑制并提高了两个临床前的D2C7-IT效率免疫能力的神经胶质瘤模型。 AIM 2：定义小胶质细胞CD40/MHCII分子是介体 D2C7-IT+αCD40抗肿瘤免疫反应。 AIM 3：确定D2C7-IT+αCD40治疗是否刺激 CD8+效应T细胞反应能够消除抗原阳性和抗原阴性肿瘤。这拟议的研究很重要，因为它将导致制定治疗策略同时肿瘤细胞杀死，TAM免疫抑制的逆转，小胶质细胞和T细胞的激活以及最终可以在诊所进行翻译和测试。