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（由申请人提供）：胶质母细胞瘤（GBM）是最常见的原发性恶性脑肿瘤，均是致命的。与受到脱靶毒性限制的现有疗法相比，免疫疗法有望提供极其精确的方法，并且效果显着。有证据表明，如果适当地重定向，T 细胞可以根除大的、已形成的肿瘤。我们开发了一种双特异性抗体，可以有效地重定向 T 细胞，以裂解表达肿瘤特异性突变的肿瘤细胞。表皮生长因子受体 (EGFRvIII) 并发现我们的分子在全身给药后定位于颅内 (IC)，介导特异性抗肿瘤免疫反应，从而根除成熟的侵袭性 IC 肿瘤，然而，迄今为止，设计用于测试 BiTE 的临床前模型已取得进展。普遍采用的异种移植系统并不理想，因为它们（1）没有考虑到自身免疫毒性的正确评估，（2）没有公平地评估潜在抑制的功效和影响。肿瘤微环境，以及（3）不允许评估潜在有益的内源性宿主免疫。在本提案中，我们将使用一种新型同基因系统进行实验，该系统直接解决上述临床相关限制。此外，与其他大分子不同，我们的数据表明。 BiTE 可能采用一种独特的机制来穿透血脑屏障 (BBB)，这可能最终会增加药物在大脑肿瘤部位的生物分布，并对与 BBB 生理学相关的其他疗法产生深远的影响。包括进一步了解 BiTE 和 T 细胞生物分布的研究，并将应用这些知识来增强 BiTE 平台对抗 IC 肿瘤的功效。肿瘤学研究，同时推进 BiTE 治疗平台，为表达 EGFRvIII 的 GBM 患者提供安全、有效的免疫治疗。这些目标的完成将为基础科学研究以及将实验疗法转化为临床所需的过程提供坚实的基础。诊所。