Systemic EGFRvIII-targeted bispecific antibody as immunotherapy for glioblastoma

 描述(申请人提供)：胶质母细胞瘤(GBM)是最常见的原发恶性脑肿瘤，通常是致命的。与目前受到靶外毒性限制的现有疗法相比，免疫疗法有望提供一种极其精确的方法，而且大量证据表明，如果适当地重新定向，T细胞可以根除大型、成熟的肿瘤。我们已经开发出一种双特异性抗体，可以有效地将T细胞重定向到表达肿瘤特异性表皮生长因子受体(EGFRvIII)突变的肿瘤细胞，并发现我们的分子在全身给药后定位于脑内(IC)，介导特异的抗肿瘤免疫反应，从而根除成熟的和侵袭性IC肿瘤。然而，到目前为止，用于测试咬合的临床前模型普遍采用了异种移植系统。这样的模型并不理想，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的抑制性肿瘤微环境的疗效和影响，以及(3)不允许对潜在有益的内源性宿主免疫进行评估。在这项提案中，我们将使用一种新的同基因系统进行实验，该系统直接解决上面概述的临床相关限制。此外，与其他大分子不同，我们的数据表明，BITS可能使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脑肿瘤部位的生物分布，并对其他与血脑屏障生理相关的治疗具有深远的影响。因此，我们纳入了进一步了解BITE和T细胞生物分布的研究，并将应用这一知识来增强BITE平台对IC肿瘤的疗效。我们的总体目标是进一步加强我作为一名内科科学家的培训，从事翻译神经肿瘤学研究，同时推进针对表达EGFRvIII的GBM患者的安全、有效免疫治疗的BITE治疗平台。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。

 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.