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:
- 金额:$ 33.23万
- 依托单位:
- 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:
- 关键词:Active ImmunotherapyAmino Acid SequenceAndrogen ReceptorAnimal ModelAntigen PresentationAntigen TargetingAntigensCD8B1 geneCancer EtiologyCancer VaccinesCellsCessation of lifeClinical TrialsCytolysisCytotoxic T-LymphocytesDNADNA VaccinesDetectionEpitopesEvaluationGenerationsGenesGlutamate Carboxypeptidase IIGoalsGrowthHLA-A2 AntigenHealthHomologous GeneHumanImmuneImmune ToleranceImmune responseImmunizationImmunotherapyIn VitroLaboratoriesLigand Binding DomainMHC Class I GenesMalignant neoplasm of prostateMetastatic Prostate CancerMethodsMissionModelingModificationMusNational Cancer InstituteNonmetastaticOther GeneticsPatientsPeptidesPhase I Clinical TrialsProstateProstate Cancer VaccineProstate-Specific AntigenProstatic NeoplasmsProteinsRattusReadingRecurrenceResearchResistanceRodentRodent ModelSafetySignal TransductionSignaling MoleculeT cell responseT-LymphocyteTherapeuticTimeTissuesTransgenic MiceTranslatingTumor AntigensUnited StatesVaccinesbasecancer therapygenetic vaccinehigh riskin vivomenmouse modelmulticatalytic endopeptidase complexnovelnovel vaccinespreclinical evaluationprostate cancer cellprostatic fraction Acid phosphatase isoenzymepublic health relevanceresponsetumorvaccine deliveryvaccine 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健康问题,需要新的治疗方法。我们的研究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。在这个应用中,我们建议评估一种新的免疫治疗靶抗原,雄激素受体的配体结合域(AR LBD),一个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,前列腺癌患者具有特异性针对AR LBD的体液和细胞免疫反应,并且特异性针对AR LBD的细胞溶解性CD8+ T细胞可以以HLA-A2 MHC i类限制的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CD8+ T细胞。此外,我们之前已经表明,Hsp72的表达增加可以增加MHC I类表达和抗原提呈。在目前的建议中,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反应,并且对DNA疫苗进行修改允许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,我们将只关注蛋白质的配体结合域(LBD),并将对特定HLA-A2表位产生反应作为免疫功效的读出,这些标记可以类似地用于人体临床试验。此外,我们将评估在DNA疫苗中编码hsp72和/或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T细胞(CTL)反应,以及体内抗肿瘤免疫反应。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疫苗在去势抵抗性非转移性前列腺癌患者中的安全性和免疫有效性,无论是否修改以促进抗原呈递。该提案的具体目的是: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CD8+ t细胞和抗前列腺肿瘤反应;2)在DNA疫苗背景下,确定Hsp72或蛋白酶体靶向信号与模型抗原的共表达是否能增强表达hla - a2的转基因小鼠的抗原特异性CD8+ t细胞效应免疫应答和抗肿瘤应答;3)确定编码AR LBD的DNA疫苗在去势抵抗性非转移性前列腺癌患者中的安全性和免疫有效性,无论是否共同表达Hsp72和/或蛋白酶体靶向信号。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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DOUGLAS G. MCNEEL其他文献
DOUGLAS G. MCNEEL的其他文献
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{{ truncateString('DOUGLAS G. MCNEEL', 18)}}的其他基金
Project 2: Androgen deprivation as an immune modulating therapy in combination with targeted immunotherapy of prostate cancer
项目2:雄激素剥夺作为免疫调节疗法与前列腺癌靶向免疫疗法相结合
- 批准号:
10555401 - 财政年份:2023
- 资助金额:
$ 33.23万 - 项目类别:
Molecular Targeted Radionuclide Therapy with Tumor-Specific Vaccine to Stimulate and Expand T-cell Activation
分子靶向放射性核素治疗与肿瘤特异性疫苗刺激和扩大 T 细胞激活
- 批准号:
10416048 - 财政年份:2020
- 资助金额:
$ 33.23万 - 项目类别:
Molecular Targeted Radionuclide Therapy with Tumor-Specific Vaccine to Stimulate and Expand T-cell Activation
分子靶向放射性核素治疗与肿瘤特异性疫苗刺激和扩大 T 细胞激活
- 批准号:
10024886 - 财政年份:2020
- 资助金额:
$ 33.23万 - 项目类别:
Molecular Targeted Radionuclide Therapy with Tumor-Specific Vaccine to Stimulate and Expand T-cell Activation
分子靶向放射性核素治疗与肿瘤特异性疫苗刺激和扩大 T 细胞激活
- 批准号:
10672943 - 财政年份:2020
- 资助金额:
$ 33.23万 - 项目类别:
Molecular Targeted Radionuclide Therapy with Tumor-Specific Vaccine to Stimulate and Expand T-cell Activation
分子靶向放射性核素治疗与肿瘤特异性疫苗刺激和扩大 T 细胞激活
- 批准号:
10263249 - 财政年份:2020
- 资助金额:
$ 33.23万 - 项目类别:
Effective Anti-Tumor Vaccination - Targeting Checkpoint Regulation at the Time of T-cell Activation
有效的抗肿瘤疫苗——T细胞激活时的靶向检查点调节
- 批准号:
9924259 - 财政年份:2017
- 资助金额:
$ 33.23万 - 项目类别:
Androgen Receptor Targeted Vaccines for Prostate Cancer
雄激素受体靶向前列腺癌疫苗
- 批准号:
8241125 - 财政年份:2010
- 资助金额:
$ 33.23万 - 项目类别:
Androgen receptor targeted vaccines for prostate cancer
雄激素受体靶向前列腺癌疫苗
- 批准号:
7982767 - 财政年份:2010
- 资助金额:
$ 33.23万 - 项目类别:
Androgen Receptor Targeted Vaccines for Prostate Cancer
雄激素受体靶向前列腺癌疫苗
- 批准号:
8657858 - 财政年份:2010
- 资助金额:
$ 33.23万 - 项目类别:
Androgen Receptor Targeted Vaccines for Prostate Cancer
雄激素受体靶向前列腺癌疫苗
- 批准号:
8089545 - 财政年份:2010
- 资助金额:
$ 33.23万 - 项目类别:
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