PHASE I TRIAL OF A PEPTIDE VACCINE AGAINST EGFRVIII

描述：(改编自研究人员摘要)表皮生长因子 受体(EGFR)在许多人类恶性肿瘤中过度表达 并被认为在这些肿瘤的肿瘤形成中发挥了作用。过度表达 受体先于基因的缺失突变或产生 受体的异常转录本。其中一个缺失突变体， EGFRvIII，具有致瘤性，构成肿瘤特异性抗原。EGFRvIII是 在15-75%的高级别星形细胞瘤、卵巢癌和胃癌以及 因此是免疫治疗的潜在靶点。 这些恶性肿瘤。表达EGFRvIII的肿瘤患者有证据表明 针对缺失突变体的抗体和T细胞免疫 因此能够将受体识别为外来抗原。临床前 小鼠模型中的数据表明，含有该基因的多肽疫苗 EGFRvIII独特的氨基酸序列可以增强人的免疫应答 细胞毒性T淋巴细胞和针对突变受体的抗体。在……里面 这些动物诱导的细胞毒性T淋巴细胞和抗体可防止 肿瘤植入并可诱导表达该受体的肿瘤消退。 针对另一个密切相关的EGFR家族成员的多肽疫苗 HER2癌蛋白，有效诱导T细胞和体液免疫， 论证了该方法的可行性。目前还没有发现辅助治疗方法 显著延长肿瘤患者的生存时间 表达EGFRvIII的组织学，作为一个群体，他们处于非常高的风险 在最初的治疗后复发的可能性。创新的预防和预防方法 这些恶性肿瘤的治疗是有必要的。这项提议的目标是 合成和合成。测试多肽疫苗，然后在 表达恶性肿瘤的EGTFRvII1患者的I期研究。的研究。 这种多肽疫苗将检测诱导T细胞和体液的能力 对该多肽的免疫及体液免疫对其表达和表达的影响 通过EGFRvIII发送信号。 这项建议的具体目标是； 1.评估免疫的安全性并确定其潜在的毒性 使用基于EGFRvIII的多肽疫苗的患者。 2.检测免疫后EGFR特异性抗体应答水平 含EGFRvIII多肽 3.人源性抗EGFRvIII抗体对EGFRvIII的影响 发信号。 4.检测免疫后EGFR特异性T细胞反应水平 与EGFRvIII多肽结合。

DESCRIPTION: (adapted from investigator's abstract) The epidermal growth factor receptor (EGFR) is overexpressed in a significant number of human malignancies and is thought to play a role in oncogenesis in these tumors. Overexpression of the receptor precedes deletional mutation of the gene or the production of aberrant transcripts for the receptor. One of these deletional mutants, EGFRvIII, is oncogenic and constitutes a tumor specific antigen. EGFRvIII is expressed in 15-75% of high grade astrocytomas, ovarian and gastric cancers and therefore represents a potential target for immunotherapy in patients with these malignancies. Patients with tumors which express EGFRvIII have evidence of antibody and T cell immunity specific to the deletional mutant and are therefore capable of recognizing the receptor as a foreign antigen. Preclinical data in a murine model demonstrates that a peptide vaccine incorporating the unique amino acid sequence of the EGFRvIII can augment an immune response of cytotoxic T lymphocytes and antibodies specific for the mutant receptor. In these animals, the induction of cytotoxic T lymphocytes and antibodies prevents tumor implantation and can induce regression of tumors expressing the receptor. Peptide vaccines targeted to another closely related EGFR family member, the HER2 oncoprotein, effectively induce T cell and humoral immunity against HER2, demonstrating feasibility of this approach. No adjuvant therapy has been found to significantly prolong the survival of patients who present with the tumor histologies which express EGFRvIII, and as a group they are at a very high risk of relapse after initial therapy. Innovative approaches to prevention and treatment of these malignancies is warranted. The objective of this proposal is to synthesize and. test peptide vaccine, followed by use of this vaccine in a phase I study in patients with EGTFRvII1 expressing malignancies. The study of this peptide vaccine will examine both the ability to induce T cell and humoral immunity to this peptide and the effect of humoral immunity on expression and signaling by EGFRvIII. The specific aims of this proposal are; 1. To evaluate the safety and define the potential toxicity of immunizing patients with an EGFRvIII based peptide vaccine. 2. To determine the level of EGFR specific antibody response after immunization with EGFRvIII peptide 3. To characterize effects of human anti-EGFRvIII antibodies on EGFRvIII signaling. 4. To determine the level of EGFR specific T cell response after immunization with EGFRvIII peptide.