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相关死亡的第五大原因。据观察，即使在手术和化疗之后，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案。口服疫苗相对容易施用。然而，疫苗的抗原成分在胃肠道中的降解是一个主要问题。在这项研究中，我们将制定并评估口服卵巢癌纳米颗粒疫苗在小鼠中预防/延缓卵巢癌生长的功效。该疫苗的抗原材料将从 ID8 鼠卵巢癌细胞系中制备，因为该细胞系在各种类似标记物方面与人类卵巢癌细胞系具有良好的相关性，并为研究卵巢癌进展和小鼠治疗前试验提供了独特的模型具有完整的免疫系统。在该提案中，卵巢癌抗原、M细胞靶向配体、免疫刺激细胞因子和Toll样受体（TLR9）配体（例如可以诱导T细胞反应的CpG寡核苷酸）将被封装在由可生物降解的纳米颗粒组成的纳米颗粒中。生物相容性聚合物基质含有肠溶聚合物和缓释聚合物的混合物，以防止其在胃中酸性条件下降解，从而能够以受控方式释放抗原。这些疫苗纳米粒子将通过口服途径给予患有卵巢肿瘤的雌性 C57BL/6 小鼠。这些颗粒靶向肠道派尔氏斑中的 M 细胞，这些细胞吸收封装的疫苗，通过将抗原呈递给树突细胞和巨噬细胞来产生免疫力。将获取血清样本以确定抗原特异性 IgG 水平，以评估全身免疫力。我们还将开展机制研究，探讨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。我们还将评估疫苗微粒的功效：a) 包括诱导 RANKL 的 M 细胞 b) 使用低剂量环磷酰胺或抗 CD25 Ab 进行 Treg 耗竭研究，以评估现有肿瘤模型中的免疫耐受性；以及 c) 过继转移T 细胞。还将评估疫苗的长期记忆反应，因为这是成功疫苗的必要组成部分。最近，纳米技术实验室的配方方法取得了重大进展，使我们能够在一步过程中使用喷雾干燥方法生产纳米粒子。从将疫苗配方从实验室推进到临床的角度来看，这是一个主要优势，因为无需进一步修改即可实现该过程的放大。