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：
8657858
负责人：
DOUGLAS G. MCNEEL
金额：
$ 34.29万
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/8657858
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

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

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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）：前列腺癌是需要新治疗的全球健康问题。我们研究的目的是开发有效的主动免疫疗法，肿瘤疫苗，以治疗前列腺癌。在此应用中，我们建议评估一种新型免疫疗法靶抗原，即雄激素受体（AR LBD）的配体结合结构域，这是一种与前列腺癌的生长和进展的生物学相关分子。我们以前已经证明，前列腺癌患者具有特异性AR LBD的体液和细胞免疫反应，并且对AR LBD特异的细胞溶解CD8+ T细胞可以在HLA-A2 MHC I限制性时尚中裂解HLA-A2 MHC的人类前列腺癌细胞。此外，我们已经证明了编码AR LBD的DNA疫苗可以在HLA-A2转基因小鼠中引起表位特异性CD8+ T细胞。此外，我们先前已经表明，HSP72的表达增加可以增加MHC I类表达和抗原表现。在当前的建议中，我们假设编码AR LBD的DNA疫苗可以引起肽特异性抗肿瘤免疫反应，并且对允许增加抗原表现的DNA疫苗的修饰可以增强抗肿瘤免疫反应。这将在HLA-A2转基因小鼠以及前列腺癌的HLA-A2表达转基因小鼠模型中进行评估。对于所有这些研究，我们将仅专注于蛋白质的配体结合结构域（LBD），并将利用对特定HLA-A2表位的反应的产生作为免疫疗效的读出，标志物可以在人类临床试验中类似地使用。此外，我们将评估编码DNA疫苗内编码HSP72和/或蛋白酶体靶向信号的DNA疫苗是否可以增加抗原呈递和抗原特异性细胞溶解T-细胞（CTL）反应，以及体内抗肿瘤的免疫反应。最后，基于这些结果，我们将进行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功效，无论是否进行任何修改以促进抗原呈递，在患有casstrate抗原，耐Castrate的非持续前列腺癌患者中。该提案的具体目的是：1）确定编码AR LBD的DNA疫苗是否可以引起HLA-A2转基因小鼠中的抗原特异性CD8+ T细胞和抗验证肿瘤反应； 2）确定在DNA疫苗的背景下，HSP72或与模型抗原的HSP72或蛋白酶体靶向信号是否可以增强HLA-A2表达的抗原特异性CD8+ T细胞效应子免疫反应和抗肿瘤反应； 3）确定编码AR LBD的DNA疫苗的安全性和免疫学疗效，无论是否共表达HSP72和/或蛋白酶体靶向信号，对casstrate耐药的非中性前列腺癌患者。