EGFR Peptides as Vaccines in Anti-Tumor Immunity

描述(申请人提供)：我们第一阶段研究的重点是开发一种新的基于多肽的疫苗策略，旨在克服对表皮生长因子受体(EGFR)肿瘤抗原的免疫耐受。EGFR的表达与肿瘤发展的严重程度直接相关，这使得这种表面蛋白成为治疗的重要靶点。事实上，EGFR在大多数实体肿瘤中都有过度表达，包括结肠癌、乳腺癌、头颈癌、非小细胞肺癌、膀胱癌、胶质瘤、肾癌、肾癌和卵巢癌。EGFR是一种约170 kDa的跨膜糖蛋白，属于erb B家族。与HER-2等家族中的其他蛋白质类似，EGFR由一个胞外受体结构域、一个跨膜区和一个具有酪氨酸激酶功能的胞内区组成。现有的针对EGFR的特异性治疗是酪氨酸激酶信号转导功能的抑制剂，以及针对EGFR蛋白的单抗Erbitux和Panitumab。抗体疗法已被观察到与传统化疗具有协同作用。这些昂贵的治疗方法会持续给患者使用，直到观察到肿瘤无反应为止。 我们的建议将检验选定的EGFR蛋白多肽打破免疫耐受和抑制EGFR-肿瘤细胞生长的能力。我们使用EGFR和HER-2多肽的初步数据支持这种方法的有效性。在第一阶段研究中： 1.我们将利用隐蔽和修饰的EGFR多肽进行免疫，并检测抗肿瘤B细胞和T细胞免疫反应的发展。 2.检测体外和体内抗肿瘤免疫对人和小鼠EGFR荷瘤细胞生长的抑制作用。 我们的工作将利用小鼠模型来比较Erbitux抗体治疗和Erbitux对EGFR多肽疫苗引起的多克隆抗体反应的抗肿瘤反应。这些研究可能会提供一种新的、易于应用的治疗策略，可以单独使用，也可以与传统的化疗联合使用，以有效和经济的方式诱导长期的抗肿瘤免疫。

DESCRIPTION (provided by applicant): The focus of our in Phase I studies is the development of a novel peptide-based vaccination strategy designed to overcome immune tolerance to Epidermal Growth Factor Receptor (EGFR) tumor antigen. The direct correlation between EGFR expression and the severity of tumor development makes this surface protein an important target of therapy. Indeed, EGFR is overexpressed in a majority of solid tumors including colon cancer, breast cancer, head-and-neck cancer, non-small-cell lung cancer, bladder carcinomas, gliomas, kidney cancer, renal cancer, and ovarian cancer. EGFR is a 170-kDa transmembrane glycoprotein of the erbB family. Similar to other proteins in this family, such as Her-2, EGFR consists of an extracellular receptor domain, a transmembrane region, and an intracellular domain with tyrosine kinase function. The existing EGFR-specific therapies are inhibitors of the tyrosine kinase signaling functions and the monoclonal antibodies, Erbitux and Panitumumab, directed at the EGFR protein. Antibody therapy has been observed to be synergistic with traditional chemotherapy. These expensive therapies are administered to patients on a continuing basis until unresponsiveness of the tumor is observed. Our proposal will examine the ability of selected peptides of the EGFR protein to break immune tolerance and inhibit EGFR-tumor cell growth. Our preliminary data from the use of both EGFR and Her-2 peptides support the efficacy of this approach. In phase I studies: 1. We will utilize cryptic and modified EGFR peptides for immunization and examine the development of both anti-tumor B and T cell immune responses. 2. We will assess the ability of anti-tumor immunity to prevent growth of human and murine EGFR-bearing tumor cells in vitro and in vivo. Our work will utilize a mouse model to compare the anti-tumor responses of Erbitux antibody therapy with Erbitux to the polyclonal antibody responses elicited by EGFR peptide vaccination. The studies will potentially provide a novel and easily applied therapeutic strategy to be used alone or in combination with traditional chemotherapies that can elicit long term anti-tumor immunity in an efficient and cost effective manner.