Extracellular Hsp70 and hyperthermia in tumor therapy

肿瘤治疗中的细胞外 Hsp70 和热疗

• 批准号: 8394481
• 负责人: STUART Keith CALDERWOOD
• 金额: $ 32.91万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-21 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394481
• 关键词: Adjuvant; Agonist; Antigen Presentation; Antigens; Binding; Biological; Breast Carcinoma; CTLA4 gene; Cancer Vaccines; Cells; Cellular Immunity; Combined Vaccines; Complex; Cross Presentation; Dendritic Cells; Fever; Heat shock proteins; Immune; Immunity; Immunotherapy; Inflammation; Ionizing radiation; Lead; Mammary Neoplasms; Mediating; Mus; Natural Immunity; Neoplasm Metastasis; Pathway interactions; Population; Property; Protein Binding; Proteins; Radiation; Radiation therapy; Regulation; Resistance; Role; Signal Transduction; Structure-Activity Relationship; T-Cell Activation; T-Lymphocyte; TLR3 gene; Toll-like receptors; Translating; Treatment Effectiveness; Tumor Immunity; Vaccine Design; Vaccines; base; cancer therapy; extracellular; human TLR3 protein; inhibitor/antagonist; killings; malignant breast neoplasm; neoplastic cell; novel vaccines; programs; receptor; translational study; tumor; uptake; vaccine effectiveness

DESCRIPTION (provided by applicant): Extracellular heat shock proteins (HSP) have been shown to have a profound effect on tumor immunity. We have prepared a highly effective cancer vaccine by extracting Hsp70/Hsp90 complexes from the fusion of tumor cells and dendritic cells (Hsp70.PC-F). We aim in this proposal to examine the properties of the vaccine and optimize its use either solo or combined with ionizing radiation. We aim first to understand the role of the receptor SRECI in dendritic cells (DC) in binding to Hsp70.PC-F and subsequent uptake and presentation of antigens to T lymphocytes. We aim to determine how SRECI can orchestrate antigen cross presentation, innate immune stimulation and cell regulation in DC. Next, in the translational studies in Aim 2 we will examine the role of Hsp70.PC-F in treatment of spontaneous mammary carcinoma in mice. We aim to determine treatment effectiveness and the degree to which vaccines can be used in combination with adjuvants such as TLR3 and TLR9 agonists as well as inhibitors of co-repressing molecule CTLA4. We will further determine whether vaccine design can be manipulated to give selective destruction of tumor initiating cells and radiation resistant cells that accumulate in fractionated radiation therapy. PUBLIC HEALTH RELEVANCE: Immunotherapy and radiation therapy, when combined, may be highly effective in cancer therapy, as radiation can kill the majority of cells in the tumor whie immunotherapy is capable of targeting small colonies of disseminated cells (metastases). We have devised a novel vaccine with unique properties based on extracting heat shock proteins from tumors and injecting them into tumor bearing mice. We will determine the effectiveness of the vaccine in killing mouse mammary tumor cells alone or in combination with biological adjuvants and ionizing radiation.

描述（由申请人提供）：细胞外热休克蛋白（HSP）已被证明对肿瘤免疫具有深远的影响。我们已经通过从肿瘤细胞和树突状细胞的融合体（Hsp 70.PC-F）中提取Hsp 70/Hsp 90复合物制备了高效的癌症疫苗。我们的目的是在这个建议，检查疫苗的特性，并优化其使用单独或结合电离辐射。我们的目的首先是了解受体SRECI在树突状细胞（DC）中结合Hsp 70.PC-F和随后的摄取和抗原呈递给T淋巴细胞的作用。我们的目的是确定SRECI如何协调抗原交叉呈递，先天免疫刺激和DC中的细胞调节。接下来，在目的2的转化研究中，我们将检查Hsp 70.PC-F在小鼠自发性乳腺癌治疗中的作用。我们的目的是确定治疗效果和疫苗可以与佐剂如TLR 3和TLR 9激动剂以及共抑制分子CTLA 4的抑制剂组合使用的程度。我们将进一步确定疫苗设计是否可以被操纵，以选择性地破坏肿瘤起始细胞和在分次放射治疗中积累的放射抗性细胞。 公共卫生相关性：当免疫疗法和放射疗法组合时，其在癌症疗法中可以是高度有效的，因为放射可以杀死肿瘤中的大多数细胞，而免疫疗法能够靶向播散细胞（转移）的小集落。我们设计了一种具有独特特性的新型疫苗，该疫苗基于从肿瘤中提取热休克蛋白并将其注射到荷瘤小鼠体内。我们将确定疫苗单独或与生物佐剂和电离辐射组合杀死小鼠乳腺肿瘤细胞的有效性。