Modified HER-2 Tumor Antigens for Vaccination in Cancer

描述(申请人提供)：乳腺癌仍然是人类最隐蔽和最难治疗的恶性肿瘤之一，每年影响成千上万的人。我们的研究旨在开发一种新的肿瘤免疫疗法，利用HER-2蛋白的隐匿肽和修饰的HER-2肽，这两种多肽都打破了对乳腺癌细胞上表达的“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。我们的第一阶段研究表明，多肽疫苗能够诱导出类似赫赛汀的抗HER-2抗体，赫赛汀是一种目前被批准用于人类乳腺癌免疫治疗的单抗。与Herceptin结合HER-2类似，多肽疫苗诱导的抗体与活肿瘤细胞上的天然HER-2蛋白结合，并在固相免疫分析中结合天然HER-2蛋白，并在其中变性HER-2蛋白和肽。我们已经证明，用HER-2多肽免疫可以在体外和体内产生抑制肿瘤细胞生长的抗体。第二阶段研究的目标是通过一组精选的HER-2多肽与批准用于人类的佐剂、明矾和新型TLR佐剂相结合，开发增强的抗HER-2肿瘤免疫。目前，抗体介导的乳腺癌治疗需要延长给药时间。这项工作将试图建立基于疫苗的长期免疫，具有与赫赛汀疗法相当的抗体特异性和生物学效力。这项研究的总体目标是开发基于多肽的疫苗策略，以模拟Herceptin的抗肿瘤特性，Herceptin是一种已被证明在乳腺癌患者中具有临床疗效的抗体。

DESCRIPTION (provided by applicant): Breast cancer remains 1 of the most insidious and difficult to treat human malignancies, affecting thousands of individuals each year. Our proposed studies are aimed at developing a novel tumor immunotherapy by using cryptic peptides of Her-2 protein and modified Her-2 peptides, both of which break immune tolerance to "self " tumor antigens expressed on breast 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. Our phase I studies have demonstrated the ability of peptide vaccination to elicit anti-Her-2 antibodies that resemble Herceptin, a monoclonal antibody currently approved for immunotherapy of human breast cancer. Similar to Her-2 binding by Herceptin, antibodies induced by peptide vaccination bind native Her-2 protein on living tumor cells and in solid phase immunoassays, as well as denatured Her-2 protein and peptides therein. We have demonstrated that immunization with Her-2 peptides elicits antibodies that inhibit tumor cell growth in vitro and in vivo. The goal of the Phase II study is to develop enhanced anti-Her-2 tumor immunity with a select group of Her-2 peptides in combination with adjuvants approved for human use, alum and novel TLR-based adjuvants. At present, antibody-mediated treatment of breast cancer requires prolonged administration of the therapeutic. This work will attempt to establish vaccine- based long term immunity with antibody specificities and biologic efficacy comparable to Herceptin therapy. The overall objective of this research is to develop peptide-based vaccination strategies to mimic the anti-tumor properties of Herceptin, an antibody with proven clinical efficacy in patients with breast cancer.