PHASE I TRIAL OF A PEPTIDE VACCINE AGAINST EGFRVIII

描述：（改编自研究者摘要）表皮生长因子 EGFR在大量人类恶性肿瘤中过度表达 并且被认为在这些肿瘤的肿瘤发生中起作用。过表达 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是致癌的并且构成肿瘤特异性抗原。EGFRvIII是 在15-75%的高级别星形细胞瘤、卵巢癌和胃癌中表达， 因此代表了免疫治疗患者的潜在靶点， 这些恶性肿瘤有证据表明，表达EGFRvIII的肿瘤患者 抗体和T细胞免疫特异性缺失突变体， 因此能够将受体识别为外源抗原。临床前 鼠模型中的数据表明， EGFRvIII的独特氨基酸序列可以增强免疫应答， 细胞毒性T淋巴细胞和突变受体特异性抗体。在 这些动物，诱导细胞毒性T淋巴细胞和抗体， 肿瘤植入，并可诱导表达该受体的肿瘤消退。 肽疫苗靶向另一个密切相关的EGFR家族成员， HER 2癌蛋白，有效诱导针对HER 2的T细胞和体液免疫， 证明了这种方法的可行性。尚未发现辅助治疗 显著延长肿瘤患者的生存期 表达EGFRvIII的组织学，作为一个群体， 复发的几率创新的预防和 这些恶性肿瘤的治疗是必要的。本提案的目的是 合成和。试验肽疫苗，然后将该疫苗用于 在表达EGTFRvII 1的恶性肿瘤患者中进行的I期研究。研究 这种肽疫苗将检测诱导T细胞和体液免疫的能力， 对该肽的免疫以及体液免疫对表达和 通过EGFRvIII信号传导。 这项建议的具体目标是： 1.评价免疫接种的安全性和潜在毒性 使用基于EGFRvIII的肽疫苗的患者。 2.确定免疫后EGFR特异性抗体应答水平 与EGFRvIII肽 3.表征人抗EGFRvIII抗体对EGFRvIII的影响 发信号。 4.确定免疫后EGFR特异性T细胞应答水平 EGFRvIII肽。

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.