Targeting Kidney Cancer-associated CD105 expression with a novel Listeria-based Vaccine Approach

使用基于李斯特菌的新型疫苗方法靶向肾癌相关 CD105 表达

基本信息

批准号：
9304467
负责人：
Laurence Michael Wood
金额：
$ 37.68万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9304467
关键词：
Active Immunotherapy Active immunity Adjuvant Adverse effects Blood Vessels Breast Cancer Model Cancer Model Cancer Patient Cancer Vaccines Cell physiology Cellular Immunity Clinical Clinical Trials Cytotoxic T-Lymphocytes DNA DNA Vaccines Data Development Disease Disease Progression ENG gene Endoglin Genes Glycoproteins Goals Health Immune response Immunity Immunotherapy In Vitro Incidence Interferons Interleukin-2 Knowledge Laboratories Life Listeria Malignant Neoplasms Malignant neoplasm of cervix uteri Mediating Methods Mission Modeling Monitor Mus Patients Pre-Clinical Model Proteins Public Health Publications Publishing Renal Cell Carcinoma Renal carcinoma Research Research Design Signal Transduction Solid T-Lymphocyte Techniques Therapeutic Therapeutic Intervention Transforming Growth Factor beta Treatment Efficacy Tumor Immunity Tumor Tissue Tumor-Associated Vasculature United States National Institutes of Health Vaccinated Vaccination Vaccines Vascular Endothelial Cell Vascularization Wood material advanced disease base cancer immunotherapy evidence base expectation improved improved outcome in vivo malignant breast neoplasm mouse model neoplasm immunotherapy neoplastic cell neovascularization novel pre-clinical preclinical development response success traditional therapy tumor tumor growth tumor progression vaccine efficacy vaccine response

项目摘要

Background. Kidney cancer is a common malignancy in the U.S. with increasing incidence. While incurable at advanced stages with traditional therapies, renal cell carcinoma(RCC), the most prevalent form of kidney cancer, is responsive to immunotherapy. However, one of the most promising type of active tumor immunotherapy, Listeria-based vaccines, is not under study for RCC. Listeria-based vaccines are highly potent inducers of anti-tumor CTLs with significant preclinical success against cervical and breast cancer and ongoing clinical trials with promising results. The PI has expertise with Listeria-based vaccines and has developed a highly effective Listeria-based vaccine targeting CD105 (endoglin), a transmembrane glycoprotein involved in TGF-β signaling that is expressed by tumor-associated vascular endothelial cells. Listeria-based vaccination targeting CD105 resulted in dramatic reductions in metastatic disease and tumor vascularization in murine breast cancer. Interestingly, in RCC, CD105 is expressed both by the tumor cells and the tumor- associated vasculature. Targeting CD105 is, therefore, a uniquely ideal strategy for RCC immunotherapy. Objective/Hypothesis. The objective in this application is to determine the efficacy of targeting RCC tumoral and vascular-associated CD105 expression with a novel Listeria-based vaccine approach. Our central hypothesis is that induction of immune responses targeting tumoral and vasculature-associated CD105 expression with Listeria-based vaccines will be an effective therapeutic intervention to eradicate RCC tumors. In addition, we hypothesize that concurrent administration of the adjuvant, ISG15, will synergize with vaccination and augment CD105-specific cytolytic T cell (CTL)-mediated anti-tumor immunity. Specific Aims. (1) To determine the therapeutic efficacy of targeting kidney cancer tumoral and vasculature- associated CD105 with Listeria-based vaccines. (2) To determine the ability of the novel adjuvant, ISG15, to augment anti-tumor CTL responses and efficacy of Listeria-based vaccines targeting kidney cancer. Study Design. We will accomplish our aims through the use of in vivo murine tumor models and in vitro studies. We will utilize murine models of RCC to monitor tumor growth, disease progression, and tumor neovascularization after administration of Listeria-based vaccines targeting CD105 as the PI and Co-I have previously performed. In addition, we will vaccinate RCC tumor-bearing mice with Listeria-based vaccines targeting CD105 concurrent with delivery of the novel protein adjuvant, ISG15. We will then determine the synergistic efficacy of this strategy using methods and techniques previously performed by the PI. Impact. These studies are expected to have an important positive impact because they will provide a strong evidence-based proof of principle for the efficacy of Listeria-based vaccines to induce therapeutic immunity against RCC, thereby, offering solid justification for the continued development of Listeria-based vaccines as a novel treatment option for RCC patients with advanced disease.

背景。肾癌在美国是常见的恶性肿瘤，发病率增加。虽然无法治愈在传统疗法的高级阶段，肾细胞癌（RCC），这是肾脏最普遍的形式癌症对免疫疗法有反应。但是，是最有前途的活性肿瘤类型之一免疫疗法，基于李斯特菌的疫苗，未接受RCC的研究。基于李斯特菌的疫苗高度高对宫颈癌和乳腺癌的临床前成功抗肿瘤CTL的有效诱导剂，以及正在进行的临床试验有希望的结果。 PI具有基于李斯特菌的疫苗的专业知识，并具有开发了一种高效的基于李斯特菌的疫苗，靶向CD105（内og），一种跨膜糖蛋白参与由肿瘤相关的血管内皮细胞表达的TGF-β信号。基于李斯特菌针对CD105的疫苗接种导致转移性疾病和肿瘤血管形成的急剧减少鼠乳腺癌。有趣的是，在RCC中，CD105既由肿瘤细胞和肿瘤表达相关的脉管系统。因此，针对CD105是RCC免疫疗法的独特理想策略。客观/假设。本应用的目的是确定靶向RCC肿瘤的效率具有新型基于李斯特菌的疫苗方法的血管相关CD105表达。我们的中心假设是诱导针对肿瘤和脉管系统相关CD105的免疫反应基于李斯特菌的疫苗的表达将是用于放射性RCC肿瘤的有效治疗干预措施。此外，我们假设调整的同时给药ISG15将与疫苗接种和增强CD105特异性细胞溶解T细胞（CTL）介导的抗肿瘤免疫性霍斯托。具体目标。（1）确定靶向肾癌肿瘤和脉管系统的治疗效率与基于李斯特菌的疫苗相关的CD105。（2）确定新颖的调整能力，即ISG15，增加抗肿瘤CTL的反应和针对肾癌的基于李斯特菌的疫苗的效率。研究设计。我们将通过使用体内鼠肿瘤模型和体外来实现目标研究。我们将利用RCC的鼠模型来监测肿瘤的生长，疾病进展和肿瘤靶向CD105作为PI和CO-1的基于李斯特菌的疫苗后，新血管化先前执行的。此外，我们将用基于李斯特菌的疫苗接种含RCC肿瘤的小鼠靶向CD105并发新型蛋白质调整，ISG15。然后，我们将确定使用PI先前执行的方法和技术的该策略的协同效率。影响。预计这些研究将产生重要的积极影响，因为它们将提供强大的基于证据的原理证明基于李斯特菌的疫苗诱导治疗免疫的效率反对RCC，从而为持续开发基于李斯特菌的疫苗提供了坚实的理由 RCC晚期疾病患者的新型治疗选择。