A Phase I Study of EGFRvIII Peptide Vaccination (CDX-110) after Conventional Radi

描述（申请人提供）：弥漫性内在脑桥胶质瘤是儿童脑肿瘤中最致命和最难治性的，中位总生存期为9-10个月。在过去的20年里，有大量的临床试验研究了不同的放疗和化疗组合和时间，但都没有显示出延长生存期的效果。我们迫切需要改进治疗方法。由于肿瘤样本的缺乏，治疗这种肿瘤的部分困难是缺乏对其基本生物学的了解。因为手术不是治疗模式的一部分，所以没有组织来源可以研究。需要改进体外研究这种肿瘤的方法。EGF受体变体III （EGFRvIII）是EGF受体最常见的变体，存在于许多不同类型的癌症中，但很少存在于正常组织中。该蛋白具有组成活性，并直接导致癌症表型。这种新的肽序列是一种理想的肿瘤抗原，是肽疫苗的基础，是治疗胶质母细胞瘤最有前途的药物之一。初始II期研究表明，与历史对照组相比，总生存率提高了一倍以上。最近的研究表明EGFRvIII在大约50%的小儿弥漫性内生性脑桥胶质瘤中表达。这些数据表明，EGFRvIII作为这些致命儿科肿瘤的靶点值得研究。在我们的研究中，我们计划进行一项I期试验，评估使用EGFRvIII肽疫苗治疗弥漫性内在脑桥胶质瘤的儿童。常规放疗后新诊断为弥漫性固有脑桥胶质瘤的儿童将每月一次皮内注射EGFRvIII肽疫苗和GM-CSF，直到疾病进展。这些患者将每月进行核磁共振成像、体格检查、免疫分析和不良事件监测。我们的目标是在这些患者中建立EGFRvIII肽疫苗接种的安全性和耐受性概况，确定接受常规放射治疗的患者的总体生存期，并评估免疫反应以探索疫苗的总体免疫原性。此外，我们计划研究弥漫性内生性脑桥胶质瘤患儿脑脊液中肿瘤微泡的分泌，以检测这些样本中的蛋白质表达和/或某些基因的改变，这些样本可作为诊断工具，并提高对该肿瘤生物学的理解。

DESCRIPTION (provided by applicant): Diffuse intrinsic pontine gliomas are the most deadly and intractable of the pediatric brain tumors with a median overall survival of 9-10 months. Over the last 20 years, there have been numerous clinical trials studying different combinations and timing of radiation and chemotherapies failing to show prolongation of survival. There is a tremendous need for improved therapeutics. Part of the difficulty with treating this tumor is a lack of understanding of its basic biology due to the paucity of tumor sample. Because surgery is not part of the treatment paradigm, there is no source of tissue to study. Improved in vitro methods of studying this tumor are needed. EGF receptor variant III (EGFRvIII) is the most common variant of the EGF receptor and is present in many different cancer types but only rarely in normal tissue. The protein is constitutively active and leads directly to a cancer phenotype. This novel peptide sequence is an ideal tumor antigen and is the basis for a peptide vaccine that is one of the most promising agents for the treatment of glioblastoma. Initial phase II studies demonstrate more than a doubling of overall survival when compared to historical controls. Recent work has shown EGFRvIII expression in about 50 percent of pediatric diffuse intrinsic pontine gliomas. This data suggests that EGFRvIII warrants investigation as a target for these deadly pediatric tumors. In our study, we plan to perform a phase I trial evaluating treatment of children with diffuse intrinsic pontine glioma using the EGFRvIII peptide vaccine. Children with newly diagnosed diffuse intrinsic pontine glioma after conventional radiation will be injected intradermally with the EGFRvIII peptide vaccine along with GM-CSF once a month until disease progression. These patients will be followed with monthly MRIs, physical exams, immunologic analysis, and adverse event monitoring. Our aims will be to establish the safety and tolerability profile of EGFRvIII peptide vaccination in these patients, determine overall survival of patients treated with the vaccine after conventional radiation, and assess immune responses to explore overall immunogenicity of the vaccine. Moreover, we plan on studying tumor microvesicle secretion into the cerebrospinal fluid of children with diffuse intrinsic pontine gliomas to examine the protein expression and/or alterations in certain genes from these samples that can be used as a diagnostic tool and improve the understanding of this tumor's biology. PUBLIC HEALTH RELEVANCE: Children diagnosed with diffuse intrinsic pontine gliomas live for only 9-10 months as there is no effective treatment. In our study we plan on performing a clinical trial in which we will treat these patients with an exciting cancer vaccine in hopes of improving the overall survival of these children. We also hope to evaluate tumor vesicles secreted into the cerebral spinal fluid of these patients in hopes of improving the understanding of this tumor's biology.