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

• 批准号: 10579973
• 负责人: Vidyalakshmi Chandramohan
• 金额: $ 40.25万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 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/10579973
• 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; Dedications; 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; Macrophage; Malignant neoplasm of brain; Mediating; Mediator; Microglia; Modeling; Molecular; Multiple Sclerosis; Mus; Oncogenes; Outcome; Patients; Phagocytosis; Phase I Clinical Trials; Phenotype; Primary Brain Neoplasms; Productivity; Radiology Specialty; Recombinant Antibody; Recurrence; Research; Role; T cell infiltration; T cell response; T-Cell Activation; T-Lymphocyte; TNFRSF5 gene; Testing; Therapeutic; Translating; Tumor Antigens; Tumor Immunity; Tumor Promotion; Tumor-associated macrophages; Variant; anti-tumor immune response; cell growth; cell killing; clinical translation; cytotoxic; cytotoxic CD8 T cells; defined contribution; effective therapy; effector T cell; glial activation; improved; in vivo; innovation; insight; 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; transcriptomic profiling; transcriptomics; tumor; tumor microenvironment; tumor-immune system interactions; tumorigenic

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/摘要 胶质母细胞瘤（GBM）是成人中最常见和最具侵袭性的原发性脑肿瘤。目前的治疗方法仍然 在改善总生存率方面不成功;因此，鉴定用于GBM的新疗法是关键的。我们有 开创了一种新的，靶向免疫毒素（IT）为基础的细胞毒性疗法，D2 C7-IT，目标是表皮生长 因子受体（EGFR）和突变型EGFR变体III（EGFRvIII），GBM的确定的驱动致癌基因。在 在临床前研究中，D2 C7-IT靶向并杀死大量的肿瘤细胞，并降低存活率， 由于存在高度免疫抑制性GBM，无法在所有治疗动物中产生治愈 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），其促进肿瘤细胞生长并抑制抗肿瘤T细胞应答。因此，我们认为， 消除TAM介导的免疫抑制预期增强D2 C7-IT诱导的抗肿瘤免疫 应答CD 40是一种免疫共刺激分子，已知其活化可再训练TAM， 也诱导T细胞反应。因此，推动本提案的中心假设是， TAM免疫抑制和通过CD 40共刺激的肿瘤促进活性将改善肿瘤的免疫抑制。 细胞毒性D2 C7-IT疗法的疗效。因此，我们的初步研究表明，（1）在 在小鼠胶质瘤模型中，D2 C7-IT+α CD 40协同作用以延长生存期并产生显著的 治疗，（2）脑内驻留的小胶质细胞是由组合激活的主要抗原呈递细胞（APC） 治疗，和（3）α CD 40治疗涉及CD 8+效应T细胞，只有当联合使用时才具有抗肿瘤性 我们的结果强烈暗示α CD 40改变TAMs的发育或活性 并激活小胶质细胞/T细胞。证明D2 C7-IT+α CD 40治疗在 相关的脑肿瘤模型并深入了解其作用机制将极大地帮助临床 D2 C7-IT+α CD 40治疗的翻译。因此，我们建议追求三个具体目标， D2 C7-IT+α CD 40抗肿瘤疗效、TAM再教育和小胶质细胞/T细胞活化机制：目的1： 在两个临床前研究中评价α CD 40是否克服TAM免疫抑制并增强D2 C7-IT疗效 免疫活性胶质瘤模型。目的2：确定小胶质细胞CD 40/MHCII分子是否为介导者 D2 C7-IT+α CD 40抗肿瘤免疫应答。目的3：确定D2 C7-IT+α CD 40治疗是否刺激 能够消除抗原阳性以及抗原阴性肿瘤的CD 8+效应T细胞应答。的 拟议的研究是重要的，因为它将导致一种治疗策略的发展， 同时杀死肿瘤细胞，逆转TAM免疫抑制，激活小胶质细胞和T细胞，以及 最终可以在临床上进行翻译和测试。