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Mechanism of Chaperone-Mediated Tumor Rejection

分子伴侣介导的肿瘤排斥机制

基本信息

批准号：
7342061
负责人：
Christopher V. Nicchitta
金额：
$ 23.95万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7342061
关键词：
Adjuvant Admixture Animals Antigen Presentation Pathway Antigen-Presenting Cells Antigens Apoptotic Binding Binding Proteins Binding Sites Breast Carcinoma CD36 gene CD8B1 gene Cancer Vaccines Cell Death Cell Maturation Cells Class Complex Dendritic Cells Disease Dose Effector Cell Endoplasmic Reticulum Engineering Environment Equilibrium Evaluation Fibroblasts Heat shock proteins Histocompatibility Histocompatibility Antigens Histocompatibility Antigens Class I Human Immune response Immune system Immunity Immunization Immunotherapeutic agent In Vitro Investigation Life Malignant Neoplasms Malignant neoplasm of kidney Mediating Metastatic Melanoma Modeling Molecular Chaperones Mus N-terminal NK Cell Activation Natural Immunity Necrosis Neonatal Neoplasm Metastasis Neoplasm Transplantation Parents Patients Pattern recognition receptor Peptides Personal Satisfaction Phase Phase III Clinical Trials Physiological Production Protocols documentation Recombinants Regulation Renal carcinoma Reporting Research Research Personnel Retroviridae Role Series Signal Pathway Signal Transduction System T-Cell Activation TSTA Testing Therapeutic Thinking Tissues Toll-Like Receptor 2 Treatment Efficacy Tumor Specific Peptide Tumor-Derived Upper arm Vaccinated Vaccination Vaccines Variant Viral base cancer therapy cell motility cell type cellular engineering cytokine human disease immunoregulation in vivo in vivo Model interest mannose receptor melanoma neonate neoplastic cell novel programs prophylactic receptor function research clinical testing research study response synthetic peptide therapeutic vaccine tumor tumor growth tumor progression vaccine efficacy

项目摘要

DESCRIPTION (provided by applicant): Vaccination with tumor-derived GRP94/gp96, the endoplasmic reticulum Hsp90 molecular chaperone, can elicit suppression of tumor growth and metastasis. The substantial therapeutic efficacy of GRP94/gp96 in prophylactic and therapeutic vaccination of mice has prompted its clinical evaluation as an immunotherapeutic for treatment of cancer in humans. Currently, GRP94/gp96 is undergoing Phase III trials for kidney cancer and melanoma. Although GRP94/gp96 has generated substantial interest as a novel immunotherapeutic, its mechanism of action remains unknown. The broad, long-term objective of the proposed research is to identify the mechanism of GRP94/gp96-mediated anti-tumor immune responses. This objective will be accomplished in the following specific aims: 1. Define the immunological basis for a gp96-secreting, cell-based tumor vaccine strategy; 2. Determine the role of gp96 and gp96 NTD in the regulation of innate immune responses. 3. Examine the role of gp96 and gp96 NTD in early immune modulation of retrovirus-induced disease. 4. Identify the effector cells and effector cell receptor(s) functioning in gp96/gp96NTD recognition and cell activation. The proposed studies will utilize a recently developed novel immunization strategy wherein animals are vaccinated with cells expressing a secretory form of GRP94/gp96. Using this experimental approach, we have demonstrated that GRP94/gp96-mediated tumor rejection is independent of the tissue of origin and thusGRP94/gp96-elicited anti-tumor immune responses can be elicited using GRP94/gp96 of non-tumor origin. Given the absence of tumor-restriction identified in these experiments, we hypothesize that GRP94/gp96functions through activation of innate immune responses. Such responses are a necessary prerequisite to robust anti-cancer adaptive immune responses. In executing the Specific Aims presented above, we will define the efficacy of the gp96-secreting, cell-based tumor vaccine strategy in multiple tumor models, using prophylactic and therapeutic immunization strategies. Detailed studies of the interactions of GRP94/gp96 with effector cells of the innate immune system will be performed. These studies will emphasize in vivo models and analyses of in vivo cellular responses. To better define the mechanism of GRP94/gp96 interaction with the innate immune system, we propose to extend analyses to the study of retrovirus-induced disease, in a neonate model, and to identification of signaling pathways accessed by GRP94/gp96.

描述（由申请人提供）：接种肿瘤源性GRP94/gp96（内质网Hsp90分子伴侣）可以抑制肿瘤生长和转移。GRP94/gp96在小鼠预防和治疗性疫苗中的显著治疗效果促使其作为一种治疗人类癌症的免疫疗法进行临床评价。目前，GRP94/gp96正在进行用于肾癌和黑色素瘤的III期临床试验。尽管GRP94/gp96作为一种新的免疫治疗药物引起了极大的兴趣，但其作用机制尚不清楚。该研究的长远目标是确定GRP94/gp96介导的抗肿瘤免疫反应的机制。这一目标将在以下几个具体目标中实现：确定分泌gp96的细胞肿瘤疫苗策略的免疫学基础；2. 确定gp96和gp96 NTD在先天免疫应答调节中的作用。3. 研究gp96和gp96 NTD在逆转录病毒诱导疾病的早期免疫调节中的作用。4. 鉴定gp96/gp96NTD识别和细胞激活中的效应细胞和效应细胞受体。