EGFR Peptides as Vaccines in Anti-Tumor Immunity

EGFR 肽作为抗肿瘤免疫疫苗

• 批准号: 8150350
• 负责人: Mark J Mamula
• 金额: $ 48.94万
• 依托单位: L2 DIAGNOSTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8150350
• 关键词: Acute; Adjuvant; Affect; Animals; Antibodies; Antigens; Applications Grants; Autoantigens; Autoimmune Process; Autoimmune Responses; Autoimmunity; B-Lymphocyte Epitopes; B-Lymphocytes; Binding; CD8-Positive T-Lymphocytes; Cancer Vaccines; Cell Adhesion; Cell Extracts; Cell Proliferation; Cells; Characteristics; Colon Carcinoma; Complement; Data; Deposition; Development; ERBB2 gene; Epidermal Growth Factor Receptor; Epitopes; Erbitux; Event; Flow Cytometry; Generations; Goals; Growth; Health; Human; Immune; Immune Tolerance; Immune response; Immunization; Immunoassay; Immunoblotting; Immunohistochemistry; Immunologics; Immunotherapeutic agent; Immunotherapy; In Vitro; Individual; Inflammation; Kinetics; Life; Link; Malignant Neoplasms; Mammary Neoplasms; Mediating; Modeling; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mus; Normal tissue morphology; Pathology; Patients; Peptides; Phase; Property; Protein Binding; Proteins; Published Comment; Roche brand of trastuzumab; Site; Solid; Structure; T memory cell; T-Lymphocyte; Therapeutic; Therapeutic Monoclonal Antibodies; Tissues; Tumor Antigens; Tumor Immunity; Tumor Tissue; Vaccination; Vaccines; aluminum sulfate; antibody-dependent cell cytotoxicity; base; cancer cell; cancer therapy; clinical efficacy; cost; human disease; improved; in vivo; inhibiting antibody; killings; neoplastic cell; novel; peptide based vaccine; phase 1 study; phase 2 study; receptor; receptor binding; response; success; theories; tumor; tumor growth; vaccination strategy

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Epidermal Growth Factor Receptor (EGFR) protein is the tumor target of approved monoclonal antibody therapies. This project will develop a candidate cancer vaccine to treat patients with aggressive tumors that express this protein. The cancer vaccine would be used in combination with existing therapies to improve long-term responses to cancer therapy.

描述（由申请人提供）：轴承肿瘤的表皮生长因子受体（EGFR）仍然是最阴险和难以治疗人类恶性肿瘤的一种，每年都会影响成千上万的人。我们提出的研究旨在通过使用EGFR蛋白的隐肽以及同甲基修饰的EGFR EGFR肽来开发新型的肿瘤免疫疗法，这两种肽都破坏了对EGFR阳性癌细胞表达的“自我”肿瘤抗原的免疫耐受性。通常，大多数肿瘤抗原已被视为正常的，非突变的自肽，将自身免疫性的概念与肿瘤免疫的发展联系起来。先前的研究表明，用异种肽抗原疫苗接种可以克服免疫耐受性。我们的第一阶段研究表明，肽疫苗接种以类似于通过Erbitux结合的方式引起抗EGFR抗体的能力，Erbitux是一种商用的单克隆抗体，目前用于人类结肠癌的免疫疗法。与Erbitux的EGFR结合类似，肽疫苗接种产生了在活肿瘤细胞和固相免疫测定中结合天然EGFR蛋白的抗体。我们已经证明，用EGFR肽免疫会引起抑制体外肿瘤生长并控制体内肿瘤生长的抗体。 II期研究的目标是通过与新型TLR基辅助剂结合选择的EGFR肽组成增强的抗EGFR肿瘤免疫。我们还将使用基于HER2的免疫治疗剂来研究基于肽的疫苗接种策略中的治疗协同作用。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期研究的目的是将基于理想的基于肽的免疫接种与TLR辅助和单克隆抗体疗法结合使用，以在人类EGFR癌的鼠模型中发展长期免疫和肿瘤清除率。 公共卫生相关性：表皮生长因子受体（EGFR）蛋白是经认可的单克隆抗体疗法的肿瘤靶标。该项目将开发一种候选癌症疫苗，以治疗表达该蛋白质的侵袭性肿瘤的患者。癌症疫苗将与现有疗法结合使用，以改善对癌症治疗的长期反应。