Androgen receptor targeted vaccines for prostate cancer

雄激素受体靶向前列腺癌疫苗

• 批准号: 7982767
• 负责人: DOUGLAS G. MCNEEL
• 金额: $ 29.3万
• 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/7982767
• 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; Essential Genes; 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。 公共卫生相关性：前列腺癌是全球重大的健康问题，也是美国男性与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。这项研究的目的是开发有效的抗肿瘤DNA疫苗作为癌症治疗，尤其是前列腺癌。因此，该提案与国家癌症研究所的使命直接相关。该建议将在前列腺癌（雄激素受体的配体结合结构域）中表征和评估新的疫苗靶抗原。 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靶标，但以前没有将其视为免疫靶标抗原。此外，我们的项目旨在通过在免疫时增加靶抗原的表现来确定提高DNA疫苗功效的方法。因此，这些研究的结果应广泛适用于其他遗传疫苗。最后，该提案将在人类临床试验中评估这些发现的患者，患有前列腺癌转移性复发风险的患者。