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

描述（由申请人提供）：弥漫性桥脑胶质瘤是最致命和最难治的儿科脑肿瘤，中位总生存期为9-10个月。在过去的20年里，有许多临床试验研究了不同的放疗和化疗组合和时间，但未能显示生存期的延长。对改进的治疗方法存在巨大的需求。治疗这种肿瘤的部分困难是由于缺乏肿瘤样本而对其基本生物学缺乏了解。由于手术不是治疗模式的一部分，因此没有组织来源可供研究。需要改进研究这种肿瘤的体外方法。 EGF受体变体III（EGFRvIII）是EGF受体的最常见变体，存在于许多不同的癌症类型中，但很少存在于正常组织中。该蛋白质是组成型活性的，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，肽疫苗是治疗胶质母细胞瘤的最有前途的药物之一。初步II期研究表明，与历史对照相比，总生存期增加了一倍以上。最近的研究表明，大约50%的儿童弥漫性脑桥胶质瘤表达EGFRvIII。这些数据表明，EGFRvIII值得作为这些致命的儿科肿瘤的靶点进行研究。 在我们的研究中，我们计划进行一项I期临床试验，评估使用EGFRvIII肽疫苗治疗弥漫性桥脑胶质瘤的疗效。常规放疗后新诊断的弥漫性脑桥内神经胶质瘤患儿将沿着GM-CSF皮内注射EGFRvIII肽疫苗，每月一次，直至疾病进展。这些患者将接受每月MRI、体格检查、免疫学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，确定常规放射治疗后接受疫苗治疗的患者的总生存期，并评估免疫应答以探索疫苗的总体免疫原性。此外，我们计划研究肿瘤微泡分泌到弥漫性内在脑桥胶质瘤儿童的脑脊液中，以检查这些样本中某些基因的蛋白质表达和/或改变，这些基因可用作诊断工具，并提高对这种肿瘤生物学的理解。 公共卫生相关性：由于没有有效的治疗方法，诊断为弥漫性桥脑胶质瘤的儿童只能活9-10个月。在我们的研究中，我们计划进行一项临床试验，我们将用一种令人兴奋的癌症疫苗治疗这些患者，希望提高这些儿童的总体生存率。我们还希望评估分泌到这些患者脑脊液中的肿瘤囊泡，以提高对这种肿瘤生物学的理解。

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.