Cytomegalovirus-based Immunotherapy for Prostate Cancer

基于巨细胞病毒的前列腺癌免疫疗法

• 批准号: 8921763
• 负责人: RICHARD B ALEXANDER
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8921763
• 关键词: Adenocarcinoma; Adult; Alleles; Animal Model; Animals; Antigens; Autoantigens; Autoimmune Process; Bacterial Artificial Chromosomes; CD4 Positive T Lymphocytes; CD8B1 gene; CTLA4 gene; Cessation of life; Characteristics; Chronic; Clinical; Clinical Data; Clinical Trials; Cytomegalovirus; Data; Development; Disease; Disease Management; Economic Inflation; Engineering; Ensure; Environment; Epitopes; Essential Genes; Flow Cytometry; Genes; Goals; Growth; HIV; HLA Antigens; Healthcare Systems; Heterophile Antigens; Histocompatibility; Human; Humor; Immune; Immune response; Immune system; Immunity; Immunization; Immunocompromised Host; Immunologic Memory; Immunotherapy; Individual; Infection; Kinetics; Laboratories; Life; Lymphoid; Lymphoid Tissue; Macaca mulatta; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Memory; Methods; Mission; Modeling; Murid herpesvirus 1; Mus; Neoplasm Metastasis; Operative Surgical Procedures; Paper; Patients; Pattern; Peptides; Phase; Phase I Clinical Trials; Phenotype; Population; Prostate; Prostate Cancer therapy; Prostate-Specific Antigen; Prostatic Neoplasms; Radiation Toxicity; Recombinants; SIV; Series; Site; Species Specificity; Structural Protein; System; Systemic Therapy; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Epitopes; Tacrolimus Binding Proteins; Testing; Transgenic Mice; Translations; Tumor Immunity; Vaccinated; Vaccine Therapy; Vaccines; Veterans; Viral; Viral Vector; Virulent; Virus; Virus Replication; Work; advanced disease; antitumor effect; base; cancer cell; cellular engineering; chemokine receptor; effective therapy; high risk; human disease; inhibitor/antagonist; men; mouse model; novel vaccines; palliative; pre-clinical; prostate cancer cell; prostate cancer model; prostatitis; public health relevance; reagent testing; receptor; research study; subcutaneous; transgenic adenocarcinoma of mouse prostate; tumor; tumor growth; tumor progression; vaccine development; vector

 DESCRIPTION (provided by applicant): Prostate cancer is a highly prevalent problem in the VA health care system. There are few therapies for men with cancer outside of the prostate; these are the men most in need of treatment because they are at the highest risk of death from the disease. This project will develop a vaccine therapy for prostate cancer using recombinant cytomegalovirus (CMV). CMV vectors are fundamentally different kind of vaccine, not just another vector because a) they are the only vector system providing persistent immune stimulation, b) anti-vector immunity is irrelevant, c) they induce a much broader T cell response directed against unconventional epitopes, d) they work even if they are spread-deficient. Finally, this is the first vector system that was able to induce an immune response that was able to control, even clear, highly virulent Simian Immunodeficiency Virus (SIV). Nothing else ever tried against this SIV has shown any similar efficacy. Recombinant CMV containing Human Immunodeficiency Virus sequences are in clinical development with spread-deficient HCMV/HIV vectors and expect to be in phase I clinical trials in 2016 in healthy adults. This proposal will explore the use of CMV-based viral vectors expressing various forms of Prostate Specific Antigen (PSA) as a therapy for prostate cancer in mice. It is clear that PSA is an antigen; it is a dominant antigen in men with autoimmune prostatitis where the immune system attacks the normal prostate. The study will utilize Transgenic Mouse Adenocarcinoma of the Prostate (TRAMP) cancer cells engineered to express PSA (TRAMP-PSA). A "humanized" mouse model of prostate cancer has been developed using TRAMP-PSA cancer cells. CMV has strong species specificity; the experiments require murine CMV (mCMV). Preliminary data showed that a murine CMV viral construct expressing PSA induced a protective anti-tumor immune response in mice challenged with TRAMP-PSA showing promise for the approach. Human CMV causes life-long infection in humans and is highly prevalent. More than half of the U.S population has been infected with CMV. While CMV rarely causes disease in healthy individuals, the virus can cause disease in immunosuppressed patients. The virus also has the potential of spreading into the environment from vaccinated patients. These characteristics present substantial hurdles to translation of a CMV-PSA vaccine into clinical use. Recent findings from several laboratories suggested that complete virus replication may not be necessary for induction and maintenance of the strong immune response against CMV. The virus can be readily engineered to be fully infectious but unable to make progeny. Such spread- deficient vectors are much more translatable to human use. The goal of current proposal is to determine whether the level of immunity induced by a spread- deficient version of the mCMV vector encoding PSA is sufficient to maintain the anti-tumor effect observed for its wild-type mCMV counterpart. The study will also determine whether the mCMV-PSA vaccine is an effective treatment for mice spontaneously developing the TRAMP tumor by starting treatment in the animals when their tumor has started to develop more closely modeling human prostate cancer. Finally, CMV will be tested in combination with the immune checkpoint inhibitor anti-CTLA4 to assess augmentation of the anti- tumor effect. The study consists of four aims: 1) To test the mCMV-PSA vectors in combination with anti- CTLA-4, 2) To test the CMV-PSA vectors in the spontaneous TRAMP mouse model more closely mimicking the human disease, 3) To characterize phenotype and function of PSA-specific CD8 and CD4 T cells induced by mCMV-PSA and, 4) To construct a spread-deficient version of mCMV-PSA and test its anti-tumor effect in transgenic mouse models of prostate cancer. The study will produce the final pre-clinical data needed to move forward with the creation of a promising therapy for prostate cancer in men.

 描述（由申请人提供）： 前列腺癌是退伍军人管理局医疗保健系统中非常普遍的问题，对于患有前列腺以外癌症的男性来说，治疗方法很少；这些男性最需要治疗，因为他们死于该疾病的风险最高。该项目将使用重组巨细胞病毒（CMV）开发前列腺癌疫苗疗法，它们是根本不同类型的疫苗，而不仅仅是另一种载体，因为a）它们是提供持久免疫刺激的唯一载体系统，b）抗载体免疫是。无关紧要，c) 他们诱导针对非常规表位的更广泛的 T 细胞反应，d) 即使它们存在传播缺陷，它们也能发挥作用。最后，这是第一个能够诱导免疫反应的载体系统，该免疫反应能够控制，甚至是清晰的、高度的。含有人类免疫缺陷病毒序列的重组巨细胞病毒（SIV）尚未在临床开发中表现出任何类似的功效。 HCMV/HIV 载体预计将于 2016 年在健康成人中进行 I 期临床试验。该提案将探索使用表达各种形式的前列腺特异性抗原 (PSA) 的基于 CMV 的病毒载体作为小鼠前列腺癌的治疗方法。很明显，PSA 是一种抗原；它是患有自身免疫性前列腺炎的男性的主要抗原，其中免疫系统会攻击正常前列腺。该研究将利用转基因小鼠前列腺腺癌 (TRAMP) 癌细胞。使用TRAMP-PSA癌细胞开发出表达PSA的“人源化”小鼠模型，该模型具有很强的物种特异性；初步数据表明，小鼠CMV。表达 PSA 的 CMV 病毒构建体在接受 TRAMP-PSA 攻击的小鼠中诱导了保护性抗肿瘤免疫反应，这表明该方法有望在人类中引起终生感染，并且在美国超过一半的地区非常流行。虽然 CMV 很少在健康个体中引起疾病​​，但该病毒也有可能从肺炎患者传播到环境中。 - PSA 疫苗投入临床使用。几个实验室的最新研究结果表明，完整的病毒复制可能不是诱导和维持针对 CMV 的强烈免疫反应所必需的。该病毒可以很容易地被设计为具有完全传染性，但无法传播后代。 - 缺乏目前提议的目标是确定编码 PSA 的 mCMV 载体的传播缺陷版本诱导的免疫水平是否足以维持其野生型所观察到的抗肿瘤效果。该研究还将确定 mCMV-PSA 疫苗是否能有效治疗自发形成 TRAMP 肿瘤的小鼠，方法是在动物的肿瘤开始发展为更接近人类前列腺癌的模型时开始治疗。组合测试使用免疫检查点抑制剂抗 CTLA4 来评估抗肿瘤效果的增强。该研究包括四个目的：1) 测试 mCMV-PSA 载体与抗 CTLA-4 的组合，2) 测试 CMV-4。自发 TRAMP 小鼠模型中的 PSA 载体更接近地模拟人类疾病，3) 表征 mCMV-PSA 诱导的 PSA 特异性 CD8 和 CD4 T 细胞的表型和功能，4) 构建传播缺陷型载体mCMV-PSA 的版本并在前列腺癌转基因小鼠模型中测试其抗肿瘤作用，该研究将产生推进创建一种有前途的男性前列腺癌疗法所需的最终临床前数据。