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

描述(申请人提供)：弥漫性固有桥脑胶质瘤是儿童脑肿瘤中最致命和最难治的，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化疗组合和时机，但都没有显示出延长生存期的结果。对改进疗法的需求是巨大的。治疗这种肿瘤的部分困难是由于肿瘤样本的缺乏而缺乏对其基本生物学的了解。因为手术不是治疗范例的一部分，所以没有组织来源可供研究。需要改进的体外方法来研究这种肿瘤。EGF受体变异体III(EGFRvIII)是EGF受体最常见的变异体，存在于许多不同类型的癌症中，但在正常组织中很少。该蛋白质在结构上是活性的，并直接导致癌症表型。这种新的多肽序列是一种理想的肿瘤抗原，也是多肽疫苗的基础，多肽疫苗是治疗胶质母细胞瘤最有前途的药物之一。最初的第二阶段研究表明，与历史对照相比，总存活率增加了一倍以上。最近的研究表明，EGFRvIII在大约50%的儿童弥漫性固有桥脑胶质瘤中表达。这一数据表明，EGFRvIII作为这些致命的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多肽疫苗治疗儿童弥漫性桥脑胶质瘤的疗效。常规放疗后新诊断为弥漫性桥脑胶质瘤的儿童将每月一次皮内注射EGFRvIII多肽疫苗和GM-CSF，直到疾病进展。这些患者将每月接受核磁共振检查、体检、免疫学分析和不良事件监测。我们的目标将是在这些患者中建立EGFRvIII肽疫苗的安全性和耐受性概况，确定接受疫苗治疗的患者在常规放射治疗后的总体存活率，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桥脑胶质瘤儿童脑脊液中肿瘤微囊的分泌，以检测这些样本中某些基因的蛋白表达和/或变化，这些基因可以作为诊断工具，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，被诊断为弥漫性桥脑神经胶质瘤的儿童只能存活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存活率。我们还希望评估这些患者脑脊液中分泌的肿瘤囊泡，以期提高对该肿瘤生物学的了解。

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.