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: 9086108
• 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 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9086108
• 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; Cytomegalovirus Infections; 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 Genes; 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; humanized mouse; 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VA医疗保健系统中一个非常普遍的问题。对于前列腺以外的癌症患者，几乎没有治疗方法;这些人最需要治疗，因为他们死于这种疾病的风险最高。该项目将开发一种使用重组巨细胞病毒（CMV）的前列腺癌疫苗疗法。 CMV载体是根本上不同种类的疫苗，而不仅仅是另一种载体，因为a）它们是提供持续免疫刺激的唯一载体系统，B）抗载体免疫是不相关的，c）它们诱导针对非常规表位的更广泛的T细胞应答，d）即使它们是扩散缺陷的，它们也起作用。最后，这是第一个能够诱导免疫应答的载体系统，该免疫应答能够控制甚至清除高毒力的猿猴免疫缺陷病毒（SIV）。没有任何其他针对这种SIV的试验显示出类似的功效。含有人类免疫缺陷病毒序列的重组CMV正在与传播缺陷型HCMV/HIV载体一起进行临床开发，预计将于2016年在健康成人中进行I期临床试验。 该提案将探索使用基于CMV的病毒载体表达各种形式的前列腺特异性抗原（PSA）作为小鼠前列腺癌的治疗。很明显，PSA是一种抗原;它是自身免疫性前列腺炎患者的主要抗原，其中免疫系统攻击正常前列腺。该研究将利用转基因小鼠前列腺癌（TRAMP）癌细胞，经工程改造以表达PSA（TRAMP-PSA）。已经使用TRAMP-PSA癌细胞开发了前列腺癌的“人源化”小鼠模型。CMV具有很强的种属特异性;实验需要鼠CMV（mCMV）。初步数据显示，表达PSA的鼠CMV病毒构建体在用TRAMP-PSA攻击的小鼠中诱导保护性抗肿瘤免疫应答，显示该方法的前景。 人CMV在人类中引起终身感染并且高度流行。超过一半的美国人感染了CMV。虽然CMV很少在健康个体中引起疾病，但该病毒可在免疫抑制患者中引起疾病。该病毒也有可能从接种疫苗的患者传播到环境中。这些特征对CMV-PSA疫苗转化为临床应用提出了实质性障碍。最近几个实验室的研究结果表明，完整的病毒复制可能不是诱导和维持针对CMV的强免疫应答所必需的。这种病毒可以很容易地被改造成具有完全感染性，但不能产生后代。这样的传播缺陷型载体更适合人类使用. 本提案的目的是确定由编码PSA的mCMV载体的扩散缺陷型诱导的免疫水平是否足以维持对其野生型mCMV对应物观察到的抗肿瘤作用。该研究还将确定mCMV-PSA疫苗是否是自发发展TRAMP肿瘤的小鼠的有效治疗方法，当它们的肿瘤开始发展更接近人类前列腺癌模型时开始治疗动物。最后，CMV将与免疫检查点抑制剂抗CTLA 4组合测试，以评估抗肿瘤作用的增强。该研究包括四个目标：1）测试与抗CTLA-4组合的mCMV-PSA载体，2）测试更接近模拟人类疾病的自发TRAMP小鼠模型中的CMV-PSA载体，3）表征由mCMV-PSA诱导的PSA特异性CD 8和CD 4 T细胞的表型和功能，（4）构建一种扩散缺陷型mCMV-PSA，并在前列腺癌转基因小鼠模型中检测其抗肿瘤作用。这项研究将产生最终的临床前数据，以推动创造一种有前途的男性前列腺癌治疗方法。