Targeting EGFRvIII in Brain Tumors with Bispecific Antibodies

描述(申请人提供)：最常见的原发恶性脑瘤，胶质母细胞瘤(GBM)，尽管手术切除，放射治疗和化疗，仍然是致命的。此外，这些传统疗法与相当大的死亡率相关，并导致周围正常脑组织和系统组织丧失能力。一种有希望的替代疗法是使用免疫疗法，该疗法已进入第三阶段临床试验，导致FDA在过去两年内批准了两种基于免疫的癌症治疗原型。大量证据表明，T细胞，特别是细胞毒性T淋巴细胞(CTL)，有能力根除大型、成熟的肿瘤，同时保持健康细胞不受影响。双特异性T细胞引擎(BITES)是一类新兴的双特异性抗体，已被证明能有效地重定向T细胞对抗肿瘤细胞。咬伤有望克服许多关键障碍，这些障碍传统上限制了免疫疗法在临床上的推广。将这一平台与其他可用的免疫治疗方法分开，我们的初步数据支持，BITE是(1)高度特异的分子，极大地降低毒性风险，(2)具有穿透血脑屏障并在脑内肿瘤中蓄积的能力，(3)可能克服GBM患者存在的多种免疫抑制机制。到目前为止，BITS之前还没有针对肿瘤特异性抗原，在我的研究之前，还没有测试它们介导抗中枢神经系统(CNS)肿瘤活性的能力。在这里，我设计了一种针对EGFRvIII肿瘤特异性抗原的咬合，并进行了临床前试验，以确定其对表达EGFRvIII的胶质母细胞瘤(GBM)的疗效。在这项提案中，我将确定有效的BITE介导的抗肿瘤反应的关键细胞成分。此外，我还探讨了咬伤将抑制性、调节性T细胞转化为具有强大抗肿瘤效应功能的免疫细胞的可能性。这项工作有可能通过产生一种新的治疗方法来改善GBM患者的临床管理。

DESCRIPTION (provided by applicant): The most common primary malignant brain tumor, glioblastoma (GBM) remains uniformly fatal despite surgical resection, radiation therapy and chemotherapy. Moreover, these conventional therapies are associated with considerable mortality and result in incapacitating damage to surrounding normal brain and system tissues. A promising alternative is the use of immunotherapy, which has ts c in phase III clinical trials, leading to pivotal approvals by the FDA of two prototypic immune-based cancer treatments within the past two years. Substantial evidence suggests that T cells, particularly cytotoxic T lymphocytes (CTLs), have the ability to eradicate large, well-established tumors while leaving healthy cells untouched. Bispecific T cell Engagers (BiTEs) represent an emerging class of bispecific antibody that has been shown to effectively redirect T cells against tumor cells. BiTEs promise to overcome many critical barriers that have traditionally limited translation of immunotherapy to the clinic. Separating this platform from other available immunotherapeutic approaches, our preliminary data support that BiTEs are (1) highly-specific molecules that greatly reduce the risk of toxicity, (2) have the ability to penetrate the BBB and accumulate in intracerebral tumors, and (3) may potentially overcome multiple mechanisms of immunosuppression present in patients with GBM. To date, BiTEs have not previously targeted tumor-specific antigens, and until my studies, have not yet been tested for their ability to mediate activity against tumors of the central nervous system (CNS). Here, I design a BiTE against the EGFRvIII tumor-specific antigen and perform preclinical tests to determine its efficacy against EGFRvIII-expressing glioblastoma (GBM). In this proposal, I will determine critical cellular components of a potent BiTE-mediated antitumor response. Furthermore, I explore the possibility that BiTEs convert suppressive, regulatory T cells into immune cells with potent antitumor effector function. This work has the potential to improve the clinical management of patients with GBM by generating a novel therapeutic.