Enhancement of HER-2/neu-based therapy using HSP110

使用 HSP110 增强基于 HER-2/neu 的治疗

• 批准号: 7038312
• 负责人: Masoud H. Manjili
• 金额: $ 22.99万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7038312
• 关键词: breast neoplasms; genetically modified animals; heat shock proteins; helper T lymphocyte; immune response; immunomodulators; intracellular; laboratory mouse; molecular chaperones; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; protooncogene; vaccine development

DESCRIPTION (provided by applicant): We have previously characterized the molecular chaperone function of a new stress protein, HSP110. We have shown that HSP110 is highly efficient in binding to substrate proteins, including tumor antigens such as HER-2/neu, by heat shock. The heat shock complex of HSP110 with the intracellular domain (ICD) of HER- 2/neu generated effective antigen-specific immune responses in a transgenic mouse model for human breast cancer. Although this immunity was capable of inhibition of the mammary tumors, complete eradication of the tumor requires an improvement in the HSP110-ICD vaccine formulation. Others (Reilly et al., 2001; Foy et al., 2002; Wolpoe et al., 2003) have reported that collaboration of both cellular and humoral HER-2/neu-targeted immune responses is required for eradication of mammary tumors. To achieve this goal, using the powerful immunoadjuvant activity of HSP110, we propose to design and evaluate a combinational vaccine of ICD plus BCD (extracellualr domain of HER-2/neu) in a chaperone complex with HSP110. We predict that generation of a strong cellular (by HSP110-ICD) and humoral (by HSP110-ECD) HER-2/neu-targeted immune responses may prevent and/or eradicate neu-overexpressing mammary tumors in a FVB-neu transgenic mouse model of human breast cancer. This hypothesis will be evaluated in Aim 1. In addition, the presence of CD4+ CD25+ regulatory T cells in breast cancer patients and FVB-neu transgenic mice may contribute to the progression of mammary tumors and failure of immunotherapy. We have recently shown that tumor-bearing animals reveal elevated CD4+ CD25+ regulatory T cells (Manjili et al., 2003). Therefore, in Aim 2, we will determine immunosuppressive function of regulatory T cells, and design and evaluate strategies, including this combinational HSP110 vaccine approach, to overcome the immunosuppressive function of regulatory T cells. The characterization of this HSP110-HER-2/neu vaccine can be expected to define new strategies for HER-2/neu-based immunotherapy of breast cancer and to have important clinical application.

描述（由申请人提供）：我们之前已经表征了新应激蛋白HSP110的分子伴侣功能。我们已经证明，HSP110 通过热休克能够高效地结合底物蛋白，包括 HER-2/neu 等肿瘤抗原。 HSP110 与 HER-2/neu 胞内结构域 (ICD) 的热休克复合物在人乳腺癌转基因小鼠模型中产生有效的抗原特异性免疫反应。尽管这种免疫力能够抑制乳腺肿瘤，但要彻底根除肿瘤，需要改进 HSP110-ICD 疫苗配方。其他人（Reilly 等人，2001；Foy 等人，2002；Wolpoe 等人，2003）报道说，根除乳腺肿瘤需要细胞和体液 HER-2/neu 靶向免疫反应的协作。为了实现这一目标，利用HSP110强大的免疫佐剂活性，我们建议设计和评估ICD加BCD（HER-2/neu的细胞外结构域）与HSP110的伴侣复合物的组合疫苗。我们预测，在 FVB-neu 转基因小鼠模型中，产生强大的细胞（通过 HSP110-ICD）和体液（通过 HSP110-ECD）HER-2/neu 靶向免疫反应可能会预防和/或根除 neu 过度表达的乳腺肿瘤人类乳腺癌。这一假设将在目标 1 中进行评估。此外，乳腺癌患者和 FVB-neu 转基因小鼠中 CD4+ CD25+ 调节性 T 细胞的存在可能导致乳腺肿瘤的进展和免疫治疗的失败。我们最近发现，荷瘤动物的 CD4+ CD25+ 调节性 T 细胞水平升高（Manjili 等，2003）。因此，在目标 2 中，我们将确定调节性 T 细胞的免疫抑制功能，并设计和评估策略，包括这种组合 HSP110 疫苗方法，以克服调节性 T 细胞的免疫抑制功能。这种 HSP110-HER-2/neu 疫苗的表征有望定义基于 HER-2/neu 的乳腺癌免疫治疗的新策略，并具有重要的临床应用。