Modified HER-2 Tumor Antigens for Vaccination in Cancer

描述（由申请人提供）：本研究旨在开发一种新的肿瘤免疫疗法，通过使用异天冬氨酸修饰的肽来打破乳腺癌细胞对“自身”肿瘤抗原的免疫耐受。大多数肿瘤抗原的特征是正常的，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，接种异种肽抗原可以克服免疫耐受。我们假设异天冬氨酸修饰的肽可以激活肿瘤反应性免疫反应，从而导致肿瘤减少或消除。我们使用小鼠自身免疫模型的初步研究支持了这一假设。异天冬氨酸修饰肽免疫产生细胞毒性（杀伤）T细胞和对“自身抗原”的体液免疫反应。提出的研究将这些观察扩展到乳腺肿瘤的转基因小鼠模型。我们将用异天冬氨酸修饰的多肽来免疫新的转基因小鼠，这些多肽代表了致癌HER-2/新“自身”肿瘤抗原中选定的表位。然后，我们将检查肿瘤特异性免疫反应，肿瘤消退和组织学在这个遗传小鼠乳腺肿瘤模型类似于人类乳腺癌。我们的长期目标是开发一种异丙基修饰的肽疫苗，以克服乳腺癌患者的免疫耐受，并将对HER-2/neu的预先免疫提高到治疗水平。

DESCRIPTION (provided by applicant): The proposed studies are aimed at developing a new tumor immunotherapy by using isoaspartyl-modified peptides to break immune tolerance to "self" tumor antigens on breast cancer cells. 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 demonstrated that vaccination with xenogenic peptide antigens could overcome immune tolerance. We hypothesize that isoaspartyl-modified peptides can activate tumor reactive immune responses that lead to tumor reduction or elimination. This hypothesis is supported by our preliminary studies using a murine model of autoimmunity. Immunization with isoaspartyl-modified peptides generated cytotoxic (killer) T cells and humoral immune responses to "self antigens." The proposed studies will extend these observations to a transgenic mouse model of mammary tumors. We will immunize neu transgenic mice with isoaspartyl-modified peptides representing selected epitopes in the oncogenic HER-2/neu "self" tumor antigen. We will then examine tumor-specific immune responses, tumor regression, and histology in this genetic mouse mammary tumor model that resembles human breast cancer. Our long-term goal is to develop an isoapartyl-modified peptide vaccine that will overcome immune tolerance in breast cancer patients, and enhance pre-existing immunity to HER-2/neu to therapeutic levels.