Nanovaccine platforms to combat pancreatic cancer

对抗胰腺癌的纳米疫苗平台

基本信息

批准号：
9979780
负责人：
MANEESH JAIN
金额：
$ 50.61万
依托单位：
IOWA STATE UNIVERSITY
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：
2017-09-25 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9979780
关键词：
Address Adjuvant Adjuvanticity Advanced Development Animal Model Antigens Antitumor Response B-Lymphocytes Blocking Antibodies Cancer Vaccines Cancer cell line Cell model Cells Consensus Cytotoxic T-Lymphocytes Data Development Diagnostic Disease Progression Early Diagnosis Engineering Environment Evaluation Exhibits Formulation Goals Human Immune Immune Tolerance Immune checkpoint inhibitor Immune response Immune system Immunization Immunologics Immunology Immunotherapeutic agent Immunotherapy Implant In Situ Lead MUC4 mucin MUC5AC gene Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Membrane Glycoproteins Methods Modality Mucin 1 protein Mucins Mus Nanotechnology Natural Immunity Pancreas Patient Care Peer Review Polyanhydrides Polyesters Polymers Positioning Attribute Process Proteins Role Signal Transduction Solid Neoplasm Structure Study models Subunit Vaccines Survival Rate T cell response Technology Testing Therapeutic Transgenic Mice Treatment Efficacy Tumor Antigens Vaccines Vertebral column amphiphilicity base cancer immunotherapy cell mediated immune response combat cytotoxic CD8 T cells design effective therapy human subject immune checkpoint blockade immunogenicity immunoregulation improved innovation insight mouse model multidisciplinary nano nanoformulation nanoparticle nanovaccine novel outcome forecast overexpression pancreatic cancer cells pancreatic cancer model pancreatic cancer patients pancreatic neoplasm preclinical study preservation programmed cell death ligand 1 programmed cell death protein 1 response targeted treatment tumor tumorigenesis vaccine candidate vaccine development vaccine efficacy

项目摘要

ABSTRACT Pancreatic cancer is one of the most lethal cancers among all solid tumors, with an extremely poor prognosis, and a dismal five-year survival rate of 7%. New insights into the regulation of immune responses and the malignant process have led to the emergence of new immunotherapeutic strategies to treat pancreatic cancer. The challenges in the development of tumor vaccines lie in the identification of tumor-associated antigens, induction of antigen-specific cell mediated immune responses, overcoming immune tolerance, and the immunosuppressive tumor environment. In this U01 application, we propose to develop novel mucin-containing nanovaccine platforms and combine them with checkpoint blockade agents that can simultaneously induce long-lived cytotoxic T lymphocyte responses and activate innate immunity and maintain the T cell response, thus overcoming the immunosuppresive environment. Among the many structural and functional transformations that occur during oncogenesis, altered expression of cell surface glycoproteins, such as mucins, presents an opportunity for the development of vaccine strategies. We propose to utilize MUC4 mucin for immunotherapeutic nano-formulations because this protein is overexpressed in >90% of pancreatic tumors and undetectable in normal pancreas (unlike the most explored mucin vaccine candidate, MUC1). Our proposed nanoadjuvant platform consists of amphiphilic polyanhydride and/or polyester nanoparticles, containing CpG, and is ideally suited for protein-based subunit vaccines. Our central hypothesis, based on significant peer-reviewed preliminary data, is that a lead nanovaccine that induces MUC4-specific, cytotoxic CD8+ T cells will therapeutically (i.e., in the presence of tumor) provide anti-tumor benefits in combination with checkpoint inhibitors. We will position this nanovaccine for preclinical studies that will advance the development of pancreatic cancer vaccine technologies by accomplishing the following Specific Aims, each of which is bounded by milestones and fallback positions: Aim 1: Formulation, optimization, and immunological characterization of MUC4-specific immune responses with nano-adjuvants. Aim 2: Evaluation of lead nanovaccine(s) and checkpoint blockade agents in a syngeneic murine model of pancreatic cancer. Aim 3: Evaluation of lead nanovaccine and checkpoint blockade agents in transgenic mouse models. At the end of the project period, we will deliver a novel nanovaccine as an effective therapy for pancreatic cancer patients. Overall the proposed studies will establish the utility of MUC4, which is the most differentially overexpressed mucin as a target for pancreatic cancer immunotherapy, and the nanotechnology and cell and animal models generated in this project will have broader applicability for evaluating other pancreatic cancer vaccine approaches.

抽象的胰腺癌是所有实体瘤中致死率最高的癌症之一，预后极差，以及 7% 的惨淡五年生存率。恶性过程导致了治疗胰腺癌的新免疫治疗策略的出现。肿瘤疫苗开发的挑战在于肿瘤相关抗原的鉴定，诱导抗原特异性细胞介导的免疫反应，克服免疫耐受，以及在此 U01 应用中，我们建议开发新型的含有粘蛋白的肿瘤环境。纳米疫苗平台并将其与检查点封锁剂结合起来，可以模拟诱导长寿命的细胞毒性 T 淋巴细胞反应并激活先天免疫并维持 T 细胞反应，从而克服了许多结构和功能中的免疫抑制环境。肿瘤发生过程中发生的转化，改变细胞表面糖蛋白的表达，例如粘蛋白，为开发疫苗策略提供了机会，我们建议利用 MUC4 粘蛋白。用于免疫治疗纳米制剂，因为该蛋白在 >90% 的胰腺肿瘤中过度表达在正常胰腺中检测不到（与我们研究最多的候选粘蛋白疫苗 MUC1 不同）。提出的纳米佐剂平台由两亲性聚酸酐和/或聚酯纳米颗粒组成，含有 CpG，非常适合基于蛋白质的亚单位疫苗。重要的同行评审初步数据是，一种诱导 MUC4 特异性、细胞毒性的先导纳米疫苗 CD8+ T 细胞将在治疗上（即在肿瘤存在的情况下）提供抗肿瘤益处我们将把这种纳米疫苗用于临床前研究，以推进通过实现以下具体目标，开发胰腺癌疫苗技术它受到里程碑和后备位置的限制：目标 1：配方、优化和免疫学纳米佐剂 MUC4 特异性免疫反应的表征目标 2：铅的评估。纳米疫苗和检查点阻断剂在同基因小鼠胰腺癌模型中的作用目标 3：在转基因小鼠模型中评估先导纳米疫苗和检查点阻断剂。项目期间，我们将提供一种新型纳米疫苗作为胰腺癌患者的有效疗法。总体而言，拟议的研究将确定 MUC4 的效用，MUC4 是差异最大的过度表达粘蛋白作为胰腺癌免疫治疗的靶标，以及纳米技术、细胞和动物模型该项目中产生的结果将具有更广泛的适用性，可用于评估其他胰腺癌疫苗接近。