Androgen Receptor Targeted Vaccines for Prostate Cancer

雄激素受体靶向前列腺癌疫苗

• 批准号: 8089545
• 负责人: DOUGLAS G. MCNEEL
• 金额: $ 28.42万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 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/8089545
• 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 cell; cancer therapy; genetic vaccine; high risk; in vivo; men; mouse model; multicatalytic endopeptidase complex; novel; novel vaccines; preclinical evaluation; prostatic fraction Acid phosphatase isoenzyme; public health relevance; response; tumor; vaccine delivery; vaccine efficacy

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. PUBLIC HEALTH RELEVANCE: Prostate cancer is a significant worldwide health problem, and the second leading cause of cancer-related death in men in the United States. New treatments for prostate cancer are urgently needed. The goal of this research is to develop effective anti-tumor DNA vaccines as a treatment for cancer, and prostate cancer in particular. Thus, this proposal is directly relevant to the mission of the National Cancer Institute. This proposal will characterize and evaluate a new vaccine target antigen in prostate cancer, the ligand binding domain of the androgen receptor. The androgen receptor has been the key pharmacological target for metastatic prostate cancer treatment for over 50 years, but there has been no previous evaluation of this as an immunological target antigen. In addition, our project seeks to identify means of increasing the efficacy of DNA vaccines by increasing presentation of the target antigen at the time of immunization. As such the results from these studies should be widely applicable to other genetic vaccines. Finally, this proposal will evaluate these findings in a human clinical trial in patients at high risk for prostate cancer metastatic recurrence.

描述（由申请人提供）：前列腺癌是一个重大的全球健康问题，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。在此应用中，我们建议评估一种新型免疫治疗靶抗原，即雄激素受体的配体结合域（AR LBD），这是一种与前列腺癌生长和进展相关的生物学分子。我们之前已经证明，前列腺癌患者存在针对 AR LBD 的体液和细胞免疫反应，并且针对 AR LBD 的溶细胞性 CD8+ T 细胞可以以 HLA-A2 MHC I 类限制的方式裂解人类前列腺癌细胞。此外，我们还证明编码 AR LBD 的 DNA 疫苗可以在 HLA-A2 转基因小鼠中诱导表位特异性 CD8+ T 细胞。此外，我们之前已经证明，Hsp72 表达的增加可以增加 MHC I 类表达和抗原呈递。在当前的提案中，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反应，并且对 DNA 疫苗进行修饰以增加抗原呈递可以增强抗肿瘤免疫反应。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估。对于所有这些研究，我们将仅关注蛋白质的配体结合域 (LBD)，并将使用对特定 HLA-A2 表位的反应生成作为免疫功效的读数，这些标记物可类似地用于人类临床试验。此外，我们将评估编码 hsp72 的 DNA 疫苗和/或 DNA 疫苗中的蛋白酶体靶向信号是否可以增强抗原呈递和抗原特异性溶细胞 T 细胞 (CTL) 反应，以及体内抗肿瘤免疫反应。最后，根据这些结果，我们将进行一项 I 期临床试验，以评估编码 AR LBD 的 DNA 疫苗（经过或不经过修饰以促进抗原呈递）在去势抵抗性非转移性前列腺癌患者中的安全性和免疫学功效。该提案的具体目标是： 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 CD8+ T 细胞和抗前列腺肿瘤反应； 2) 确定在 DNA 疫苗中 Hsp72 或蛋白酶体靶向信号与模型抗原的共表达是否可以增强表达 HLA-A2 的转基因小鼠中抗原特异性 CD8+ T 细胞效应免疫反应和抗肿瘤反应； 3) 确定编码 AR LBD 的 DNA 疫苗（有或没有 Hsp72 和/或蛋白酶体靶向信号的共表达）在去势抵抗性非转移性前列腺癌患者中的安全性和免疫学功效。 公共健康相关性：前列腺癌是一个重大的全球健康问题，也是美国男性癌症相关死亡的第二大原因。迫切需要针对前列腺癌的新疗法。这项研究的目标是开发有效的抗肿瘤 DNA 疫苗来治疗癌症，特别是前列腺癌。因此，该提案与国家癌症研究所的使命直接相关。该提案将表征和评估前列腺癌中的新疫苗靶抗原，即雄激素受体的配体结合域。 50 多年来，雄激素受体一直是转移性前列腺癌治疗的关键药理学靶点，但之前尚未对其作为免疫学靶抗原进行过评估。此外，我们的项目旨在通过增加免疫时目标抗原的呈现来确定提高 DNA 疫苗功效的方法。因此，这些研究的结果应该广泛适用于其他基因疫苗。最后，该提案将在前列腺癌转移复发高风险患者的人体临床试验中评估这些发现。