Androgen receptor targeted vaccines for 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。我们之前已经证明，前列腺癌患者存在对AR LBD特异性的体液和细胞免疫反应，并且对AR LBD特异性的溶细胞CD 8 + T细胞可以以HLA-A2 MHC I类限制性方式溶解人前列腺癌细胞。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。 公共卫生相关性：前列腺癌是一个重要的全球性健康问题，也是美国男性癌症相关死亡的第二大原因。前列腺癌的新治疗方法是迫切需要的。这项研究的目标是开发有效的抗肿瘤DNA疫苗作为癌症，特别是前列腺癌的治疗方法。因此，这项建议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，雄激素受体的配体结合域。雄激素受体是转移性前列腺癌治疗的关键药理学靶点已有50多年，但以前没有将其作为免疫学靶抗原进行评估。此外，我们的项目旨在确定通过在免疫时增加靶抗原的呈递来提高DNA疫苗效力的方法。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。

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.