EGFR Peptides as Vaccines in Anti-Tumor Immunity

携带表皮生长因子受体(EGFR)的肿瘤仍然是人类最隐蔽和最难治疗的恶性肿瘤之一，每年影响数以千计的人。我们的研究旨在通过使用EGFR蛋白的隐匿肽和异天冬氨酸修饰的EGFR多肽来开发新的肿瘤免疫疗法，这两种多肽都打破了对表达在EGFR阳性癌细胞上的“自身”肿瘤抗原的免疫耐受。一般说来，大多数肿瘤抗原都是正常的、非突变的自体肽，将自身免疫的概念与肿瘤免疫的发展联系在一起。以往的研究表明，接种异源多肽抗原可以克服免疫耐受。我们的第一阶段研究证明，多肽疫苗能够诱导抗EGFR抗体，其方式类似于Erbitux与肿瘤细胞的结合，Erbitux是一种目前用于人类结肠癌免疫治疗的商用单抗。与Erbitux的EGFR结合类似，多肽疫苗产生的抗体可以在活肿瘤细胞上结合本地EGFR蛋白，并在固相免疫分析中进行。我们已经证明，用EGFR多肽免疫可以在体外诱导抑制肿瘤生长的抗体，并在体内控制肿瘤生长。第二阶段研究的目标是通过一组精选的EGFR多肽与新型TLR佐剂相结合，开发增强的抗EGFR肿瘤免疫。我们还将研究我们的基于多肽的疫苗接种策略与基于HER2的免疫疗法的治疗协同效应。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。第二阶段研究的目标是将理想的基于多肽的免疫与TLR佐剂和单抗治疗相结合，以在人EGFR癌症的小鼠模型中发展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.