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Androgen Receptor Targeted Vaccines for Prostate Cancer

雄激素受体靶向前列腺癌疫苗

基本信息

批准号：
8453470
负责人：
DOUGLAS G. MCNEEL
金额：
$ 33.23万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-14 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8453470
关键词：
Active Immunotherapy Amino Acid Sequence Androgen Receptor Animal Model Antigen Presentation Antigen Targeting Antigens CD8B1 gene Cancer Etiology Cancer Vaccines Cells Cessation of life Clinical Trials Cytolysis Cytotoxic T-Lymphocytes DNA DNA Vaccines Detection Epitopes Evaluation Generations Genes Glutamate Carboxypeptidase II Goals Growth HLA-A2 Antigen Health Homologous Gene Human Immune Immune Tolerance Immune response Immunization Immunotherapy In Vitro Laboratories Ligand Binding Domain MHC Class I Genes Malignant neoplasm of prostate Metastatic Prostate Cancer Methods Mission Modeling Modification Mus National Cancer Institute Nonmetastatic Other Genetics Patients Peptides Phase I Clinical Trials Prostate Prostate Cancer Vaccine Prostate-Specific Antigen Prostatic Neoplasms Proteins Rattus Reading Recurrence Research Resistance Rodent Rodent Model Safety Signal Transduction Signaling Molecule T cell response T-Lymphocyte Therapeutic Time Tissues Transgenic Mice Translating Tumor Antigens United States Vaccines base cancer therapy genetic vaccine high risk in vivo men mouse model multicatalytic endopeptidase complex novel novel vaccines preclinical evaluation prostate cancer cell prostatic fraction Acid phosphatase isoenzyme public health relevance response tumor vaccine delivery vaccine efficacy

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer is a significant worldwide health problem for which new treatments are needed. The goal of our research is to develop effective active immunotherapies, tumor vaccines, as a treatment for prostate cancer. In this application we propose to evaluate a novel immunotherapy target antigen, the ligand-binding domain of the androgen receptor (AR LBD), a biologically relevant molecule to prostate cancer growth and progression. We have previously demonstrated that patients with prostate cancer have existing humoral and cellular immune responses specific for the AR LBD, and that cytolytic CD8+ T cells specific for the AR LBD can lyse human prostate cancer cells in an HLA-A2 MHC class I-restricted fashion. In addition, we have demonstrated that a DNA vaccine encoding the AR LBD can elicit epitope-specific CD8+ T cells in an HLA-A2 transgenic mouse. Moreover, we have previously shown that increased expression of Hsp72 can increase MHC class I expression and antigen presentation. In the current proposal we hypothesize that a DNA vaccine encoding the AR LBD can elicit peptide- specific anti-tumor immune responses, and that modifications to a DNA vaccine permitting increased antigen presentation can augment anti-tumor immune responses. This will be evaluated in HLA-A2 transgenic mice, and in an HLA-A2-expressing transgenic mouse model of prostate cancer. For all of these studies we will focus on the ligand-binding domain (LBD) of the protein only, and will use the generation of responses to specific HLA-A2 epitopes as a read-out for immunological efficacy, markers which can be similarly used in a human clinical trial. In addition, we will evaluate whether DNA vaccines encoding hsp72 and/or a proteasome-targeting signal within a DNA vaccine can augment antigen presentation and antigen-specific cytolytic T- cell (CTL) responses, and anti-tumor immune responses in vivo. Finally, based on these results, we will conduct a phase I clinical trial to evaluate the safety and immunological efficacy of a DNA vaccine encoding the AR LBD, with or without modifications to facilitate antigen presentation, in patients with castrate-resistant, nonmetastatic prostate cancer. The specific aims of the proposal will be: 1) to determine whether a DNA vaccine encoding the AR LBD can elicit antigen-specific CD8+ T-cells and anti-prostate tumor responses in HLA-A2 transgenic mice; 2) to determine whether co-expression of Hsp72 or a proteasome-targeting signal with a model antigen in the context of a DNA vaccine can augment antigen-specific CD8+ T-cell effector immune responses and anti-tumor responses in HLA-A2-expressing transgenic mice; and 3) to determine the safety and immunological efficacy of a DNA vaccine encoding the AR LBD, with or without co-expression of Hsp72 and/or a proteasome-targeting signal, in patients with castrate-resistant nonmetastatic prostate cancer.

描述（由申请人提供）：前列腺癌是一个重要的全球性健康问题，需要新的治疗方法。我们研究的目标是开发有效的主动免疫疗法，肿瘤疫苗，作为前列腺癌的治疗方法。在本申请中，我们提出评估一种新的免疫治疗靶抗原，雄激素受体（AR LBD）的配体结合结构域，一种与前列腺癌生长和进展相关的生物学分子。我们先前已经证明，前列腺癌患者具有对AR LBD特异性的现有体液和细胞免疫应答，并且对AR LBD特异性的溶细胞CD 8 + T细胞可以以HLA-A2 MHC I类限制性方式裂解人前列腺癌细胞。此外，我们已经证明，编码AR LBD的DNA疫苗可以在HLA-A2转基因小鼠中引发表位特异性CD 8 + T细胞。此外，我们以前已经表明，增加Hsp 72的表达可以增加MHC I类表达和抗原呈递。在当前的提议中，我们假设编码AR LBD的DNA疫苗可以引发肽特异性抗肿瘤免疫应答，并且对允许增加抗原呈递的DNA疫苗的修饰可以增强抗肿瘤免疫应答。这将在HLA-A2转基因小鼠和表达HLA-A2的前列腺癌转基因小鼠模型中进行评价。对于所有这些研究，我们将仅关注蛋白质的配体结合结构域（LBD），并将使用对特定HLA-A2表位的反应的产生作为免疫功效的读出，这些标记物可以类似地用于人类临床试验。此外，我们将评估编码hsp 72和/或DNA疫苗内的蛋白酶体靶向信号的DNA疫苗是否可以增强抗原呈递和抗原特异性细胞溶解性T细胞（CTL）应答以及体内抗肿瘤免疫应答。最后，基于这些结果，我们将进行一项I期临床试验，以评估编码AR LBD的DNA疫苗的安全性和免疫学疗效，有或没有修改，以促进抗原呈递，在去势抵抗，非转移性前列腺癌患者。本发明的具体目的是：1）确定编码AR LBD的DNA疫苗是否可以在HLA-A2转基因小鼠中引发抗原特异性CD 8 + T细胞和抗前列腺肿瘤应答; 2）确定在DNA疫苗的情况下，Hsp 72或蛋白酶体靶向信号与模型抗原的共表达是否可以增强抗原特异性CD 8 + T细胞效应免疫应答和抗-CD 8 + T细胞效应免疫应答。在表达HLA-A2的转基因小鼠中的肿瘤应答;和3）确定编码AR LBD的DNA疫苗（有或没有Hsp 72和/或蛋白酶体靶向信号的共表达）在患有去势抵抗性非转移性前列腺癌的患者中的安全性和免疫功效。