EGFR Peptides as Vaccines in Anti-Tumor Immunity

携带表皮生长因子受体（EGFR）的肿瘤仍然是最潜伏且最难治疗的人类恶性肿瘤之一，每年影响数千人。我们提出的研究旨在通过使用EGFR蛋白的隐蔽肽以及异戊酰基修饰的EGFR肽来开发新的肿瘤免疫疗法，这两种肽都打破了对EGFR阳性癌细胞上表达的“自身”肿瘤抗原的免疫耐受。一般来说，大多数肿瘤抗原被表征为正常的、非突变的自身肽，将自身免疫的概念与肿瘤免疫的发展联系起来。以往的研究表明，用异种肽抗原接种可以克服免疫耐受。我们的I期研究已经证明了肽疫苗接种以类似于Erbitux结合肿瘤细胞的方式引发抗EGFR抗体的能力，Erbitux是目前用于人结肠癌免疫治疗的商业单克隆抗体。与爱必妥的EGFR结合类似，肽疫苗接种产生的抗体结合活肿瘤细胞上和固相免疫测定中的天然EGFR蛋白。我们已经证明，免疫与EGFR肽eliminates抗体，抑制肿瘤生长在体外和控制肿瘤生长在体内。II期研究的目标是使用一组精选的EGFR肽与新型TLR佐剂联合开发增强的抗EGFR肿瘤免疫力。我们还将检查我们的基于肽的疫苗接种策略与基于HER2的免疫治疗剂的治疗协同作用。为了支持我们自己的方法，最近的研究表明，许多肿瘤类型共表达EGFR和HER2蛋白。II期研究的目标是匹配理想的基于肽的免疫与TLR佐剂和单克隆抗体治疗的组合，以在人EGFR癌症的鼠模型中开发长期免疫和肿瘤清除。

Epidermal Growth Factor Receptor (EGFR) bearing tumors remain as one of the most insidious and difficult to treat human malignancies, affecting thousands of individuals each year. Our proposed studies are aimed at developing novel tumor immunotherapy by using both cryptic peptides of EGFR protein as well as isoaspartyl modified EGFR peptides, both of which break immune tolerance to "self" tumor antigens expressed on EGFR positive cancer cells. In general, most tumor antigens have been characterized as normal, non-mutated self-peptides, linking the concepts of autoimmunity with the development of tumor immunity. Previous studies demonstrate that vaccination with xenogenic peptide antigens can overcome immune tolerance. Our phase I studies have demonstrated the ability of peptide vaccination to elicit anti-EGFR antibodies in a manner that resembles binding of tumor cells by Erbitux, a commercial monoclonal antibody currently used in the immunotherapy of human colon cancer. Similar to EGFR binding by Erbitux, peptide vaccination generated antibody that binds native EGFR protein on living tumor cells and in solid phase immunoassays. We have demonstrated that immunization with EGFR peptides elicits antibodies that inhibit tumor growth in vitro and control tumor growth in vivo. The goals of the Phase II study are to develop enhanced anti-EGFR tumor immunity with a select group of EGFR peptides in combination with novel TLR-based adjuvants. We will also examine the therapeutic synergy in our peptide-based vaccination strategy with HER2 based immunotherapeutics. In support of our own approaches, recent studies have demonstrated that many tumor types co-express EGFR as well as HER2 protein. It is the goal of the Phase II studies to match the ideal peptide based immunizations in combination with TLR adjuvant and monoclonal antibody therapy to develop long term immunity and tumor clearance in murine models of human EGFR cancers.