Systemic EGFRvIII-targeted bispecific antibody as immunotherapy for glioblastoma

全身性 EGFRvIII 靶向双特异性抗体作为胶质母细胞瘤的免疫疗法

• 批准号: 9212119
• 负责人: Patrick C Gedeon
• 金额: $ 4.9万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9212119
• 关键词: Address; Adoptive Transfer; Antibodies; Antigens; Autoimmune Process; B-Lymphocytes; Basic Science; Biodistribution; Bispecific Antibodies; Blood - brain barrier anatomy; Brain; Brain Neoplasms; CD19 gene; CD3 Antigens; Cancer Etiology; Cell Therapy; Clinic; Clinical Trials; Common Neoplasm; Cytolysis; Data; Dose-Limiting; Epidermal Growth Factor Receptor; Evaluation; Experimental Designs; Exposure to; Fostering; Foundations; Glioblastoma; Goals; Human; Immune response; Immunity; Immunocompetent; Immunoglobulin Fragments; Immunotherapy; Intracranial Neoplasms; Investigational Therapies; Knowledge; Ligands; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Manuscripts; Mediating; Methods; Modeling; Mus; Mutation; Neuraxis; Non-Hodgkin' s Lymphoma; Normal tissue morphology; Patients; Pharmaceutical Preparations; Physicians; Physiology; Pre-Clinical Model; Primary Brain Neoplasms; Process; Protein Tyrosine Kinase; Public Health; Publishing; Quality of life; Recombinant Antibody; Reporting; Research; Research Design; Resistance; Scientist; Site; Surface; Syndrome; System; T-Cell Activation; T-Lymphocyte; Techniques; Technology; Testing; Therapeutic; Toxic effect; Training; Translating; Tumor Antigens; Tumor Tissue; United States National Academy of Sciences; Vaccines; Viral; Xenograft procedure; base; career; cell growth; cell motility; childhood cancer mortality; clinically relevant; cytokine; drug distribution; epidermal growth factor receptor VIII; experimental study; immunological synapse; improved; macromolecule; model design; mouse model; neoplastic cell; neuro-oncology; novel; outcome forecast; public health relevance; tumor; tumor microenvironment; young adult

 DESCRIPTION (provided by applicant): Glioblastoma (GBM), the most common of the primary malignant brain tumors, is uniformly fatal. In contrast to current therapy, which is limite by off-target toxicity, immunotherapy promises an exquisitely precise approach, and substantial evidence indicates that, if appropriately redirected, T cells can eradicate large, well- establishe tumors. We have developed a bispecific antibody that effectively redirects T cells to lyse tumor cells expressing a tumor-specific mutation of the epidermal growth factor receptor (EGFRvIII) and found that our molecule localizes intracranially (IC) following systemic administration, mediating specific anti-tumor immune responses that eradicate well-established and invasive IC tumors. Preclinical models designed to test BiTEs to date, however, have universally employed xenograft systems. Such models are not ideal as they (1) do not account for proper evaluation of autoimmune toxicity, (2) do not fairly assess efficacy and the impact of a potentially suppressive tumor microenvironment, and (3) do not permit evaluation of potentially beneficial endogenous host immunity. In this proposal, we will conduct experiments employing a novel syngeneic system that directly addresses the clinically relevant limitations outlined above. Additionally, unlike other macromolecules, our data suggest that BiTEs may employ a unique mechanism to penetrate the blood-brain barrier (BBB), which may ultimately increase the biodistribution of the drug at tumor sites in the brain and have far-reaching implications for othe therapies where BBB physiology is relevant. We therefore include studies to further our understanding of BiTE and T-cell biodistribution and will apply this knowledge to enhance the efficacy of the BiTE platform against IC tumors. Our overall goal is to further my training as a physician-scientist pursuing a career in translational neuro- oncology research while advancing the BiTE therapeutic platform for safe, effective immunotherapy in patients with EGFRvIII-expressing GBM. The completion of these aims will provide a strong foundation in basic science research as well as exposure to processes necessary to translate an experimental therapy to the clinic.

 描述（由适用提供）：胶质母细胞瘤（GBM）是原发性恶性脑肿瘤中最常见的致命性。与当前疗法受到脱靶毒性限制的当前疗法相反，免疫疗法有望准确的方法，并且大量证据表明，如果适当地重定向，则T细胞可以播放大型，良好的肿瘤。我们已经开发了一种双特异性抗体，该抗体有效地将T细胞重定向到表达表皮生长因子受体（EGFRVIII）的肿瘤特异性突变的肿瘤细胞，并发现我们的分子在全身施用后颅内（IC）定位于全身性施用，介导了特定的抗肿瘤免疫反应，从而介导了良好的放射线良好的良好孔，并构成了良好的构造。然而，旨在测试叮咬的临床前模型已普遍采用异种移植系统。这样的模型并不理想，因为它们（1）不考虑自身免疫性毒性的正确评估，（2）不能公平地评估有效性和潜在抑制性肿瘤微环境的影响，并且（3）不允许评估潜在的有益的内源性内源性宿主免疫史。在此提案中，我们将采用一种新型的合成系统进行实验，该系统直接解决上述临床相关的局限性。此外，与其他大分子不同，我们的数据表明，叮咬可能采用独特的机制来穿透血脑屏障（BBB），这最终可能会增加大脑中肿瘤部位的药物生物分布，并且对BBB物理学相关的OTHE疗法具有深远的影响。因此，我们包括研究以进一步了解咬合和T细胞生物分布，并将应用此知识来提高咬合平台对IC肿瘤的效率。我们的总体目标是进一步作为一名医师科学家的培训，从事转化神经肿瘤研究职业，同时推进EGFRVIII-Exparting GBM患者的安全有效免疫疗法的咬合疗法平台。这些目标的完成将为基础科学研究和暴露于将实验疗法转化为诊所所必需的过程。