Ovarian cancer using novel nanoparticle formulations

使用新型纳米颗粒制剂治疗卵巢癌

基本信息

批准号：
8903749
负责人：
Maurizio Chiriva-Internati
金额：
$ 10.18万
依托单位：
KIROMIC, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-04 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8903749
关键词：
Acetates Adoptive Transfer Aftercare Animal Cancer Model Animals Antibodies Antibody Response Antigens B-Lymphocytes Bacterial DNA Biological Assay C57BL/6 Mouse CD8B1 gene Cancer Etiology Cancer Relapse Cancer Vaccines Cancer cell line Cell Line Cellulose Cessation of life Charge Cyclodextrins Cyclophosphamide Cytotoxic T-Lymphocytes DNA Sequence Data Dendritic Cells Development Dose Drug Formulations Encapsulated Engineering Enteral Female Generations Growth Health Human IL2RA gene Immune Immune response Immune system Immunity Immunoglobulin G Immunologic Tests Immunotherapeutic agent Interleukin-12 Interleukin-2 Intestines Kinetics Laboratories Life Ligands M cell Malignant Neoplasms Malignant neoplasm of ovary Measures Mediating Memory Methodology Methods Methylcellulose Modeling Modification Mus Nanotechnology Natural Killer Cells Needles Oligonucleotides One-Step dentin bonding system Operative Surgical Procedures Oral Particulate Polymers Preparation Process Proteins Recurrence Regulatory T-Lymphocyte Research Research Project Grants Role Route Sampling Serum Stomach Structure of aggregated lymphoid follicle of small intestine Succinates Surface System T cell response T-Cell Proliferation T-Lymphocyte TNFSF11 gene Testing Therapeutic Trials Time Toll-like receptors Treatment Efficacy Tumor Immunity Vaccinated Vaccination Vaccine Antigen Vaccines Woman base bench to bedside biocompatible polymer biodegradable polymer cancer cell chemotherapy cytokine design efficacy testing immunogenic immunogenicity long term memory macrophage manufacturing process mouse model nanoparticle nanoparticulate neoplastic cell novel oral vaccine ovarian neoplasm particle pre-clinical prevent research study response scale up tumor tumor progression vaccine delivery vaccine development vaccine efficacy vaccine response

项目摘要

DESCRIPTION (provided by applicant): Ovarian cancer is the fifth most leading cause of cancer related deaths in women in the US. It has been observed that the cancer relapses within relatively short periods of time even after the surgery and chemotherapy. Therefore, immunotherapeutic strategies may serve as an alternative to control the recurrence or progression of ovarian cancer. Oral vaccines are relatively easy to administer. However, the degradation of the antigenic component of the vaccine in the gastro-intestinal tract is a major problem. In this research study, we will formulate and evaluate the efficacy of oral ovarian cancer nanoparticulate vaccine in mice to prevent/retard the ovarian cancer growth. The antigenic material for the vaccine will be prepared from ID8 murine ovarian cancer cells as this cell line correlates well with human ovarian cancer cell lines in terms of various similar markers and provides a unique model to study ovarian cancer progression and pre-therapeutic trials in mice with intact immune systems. In this proposal, ovarian cancer antigens, M-cell targeting ligands, immuno-stimulatory cytokines and toll-like receptor (TLR9) ligands such as CpG oligonucleotide that can induce T-cell responses, will be encapsulated into nanoparticles made up of a biodegradable and biocompatible polymer matrix containing a mixture of an enteric polymer to prevent their degradation under acidic conditions in the stomach and also a sustained release polymer enabling the release of the antigen in a controlled manner. These vaccine nanoparticles will be administered to female C57BL/6 mice with ovarian tumors by the oral route. These particles are targeted to M-cells present in Peyer's patches in the intestine, which take up the encapsulated vaccine to generate immunity by presenting the antigen to dendritic cells and macrophages. Serum samples will be obtained to determine the antigen specific IgG levels to assess the systemic immunity. We will also carry out mechanistic studies to investigate the role of CD+ T-cells, CD8+ T-cells, NK cells, and B cells in anti-tumor immunity induced by the oral vaccines. We will also evaluate the efficacy of the vaccine microparticles after a) including M-cell inducing RANKL b) Treg depletion studies with low dose of cyclophosphamide or anti-CD25 Ab in order to evaluate immunotolerance in pre-existing tumor models and c) adoptive transfer of T-cells. Long-term memory responses of the vaccine will also be assessed since this is a necessary component of a successful vaccine. Recently, major advances have been made in the formulation methodology at the Nanotechnology Laboratory allowing us to produce nanoparticles using the spray drying methodology in a single step process. This is a major advantage from the standpoint of advancing the vaccine formulation from bench to clinic as scale-up of this process can be achieved with no further modifications.

描述（由申请人提供）：卵巢癌是美国女性癌症与癌症相关死亡的第五大主要原因。已经观察到，即使在手术和化疗后，癌症也会在相对较短的时间内复发。因此，免疫治疗策略可以作为控制卵巢癌复发或进展的替代方法。口服疫苗相对容易施用。但是，胃肠道中疫苗的抗原成分降解是一个主要问题。在这项研究中，我们将制定和评估口腔卵巢癌在小鼠中的卵巢癌疫苗的功效，以防止/阻断卵巢癌的生长。该疫苗的抗原材料将从ID8鼠卵巢癌细胞中制备，因为该细胞系与人类卵巢癌细胞系的各种相似标记良好相关，并提供了一个独特的模型，可用于研究卵巢癌的进展和具有完整免疫系统的小鼠的卵巢癌进展和治疗前试验。在这一提议中，卵巢癌抗原，靶向配体的M细胞，免疫刺激性细胞因子和收费受体（TLR9）的配体（例如CpG）可以诱导T-CELL反应的CpG寡核苷酸，这些配体可诱导纳米杂质组成的纳米果实，并将其组成的纳米杂质组成，并将其组成的液体组合成液体组合。防止它们在胃中的酸性条件下降解，还可以持续释放聚合物，以便以受控的方式释放抗原。这些疫苗纳米颗粒将通过口腔途径和卵巢肿瘤对雌性C57BL/6小鼠施用。这些颗粒针对肠道中佩耶斑块中存在的M细胞，这些颗粒通过将抗原呈现对树突状细胞和巨噬细胞的抗原来吸收封装的疫苗以产生免疫力。将获得血清样品以确定抗原特异性IgG水平以评估系统性免疫。我们还将进行机械研究，以研究CD+ T细胞，CD8+ T细胞，NK细胞和B细胞在口服疫苗诱导的抗肿瘤免疫中的作用。我们还将评估a）疫苗微粒的疗效，包括M细胞诱导RANKL b）使用低剂量的环磷酰胺或抗CD25 AB的TREG耗竭研究，以评估预灭肿瘤模型中的免疫耐药性和c）T-cells的产物传递。由于这是成功疫苗的必要组成部分，还将评估疫苗的长期记忆反应。最近，在纳米技术实验室的制剂方法中取得了重大进展，使我们能够在单个步骤过程中使用喷雾干燥方法生产纳米颗粒。从推进疫苗配方从长凳到诊所的疫苗配方的角度来看，这是一个主要优势，因为可以在没有进一步修改的情况下实现此过程的扩大。