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Transarterial Immunomodulatory Embolization: A novel approach to cancer therapy

经动脉免疫调节栓塞：癌症治疗的新方法

基本信息

批准号：
9555090
负责人：
Guillermo Antonio Ameer
金额：
$ 5.23万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9555090
关键词：
Adenosine Adverse effects Agonist Animal Model Antigens Antioxidants Apoptosis Apoptotic Autoimmunity Biochemical Biocompatible Materials Biological Biomedical Engineering Cancer Model Catheters Cell Death Cells Chemoembolization Citrates Clinical Contrast Media Data Detection Development Doxorubicin Drug Controls Drug Delivery Systems Eligibility Determination Foundations Gel Goals Home environment Homeostasis Imiquimod Immune Immune response Immune system Immunologic Adjuvants Immunomodulators Immunosuppression Immunotherapy Inflammatory Intercellular Fluid Intervention Lead Lesion Liver Liver neoplasms Lymphangiogenesis Malignant - descriptor Malignant Neoplasms Malignant neoplasm of liver Medicine Minimally Invasive Surgical Procedures Modeling Molecular Weight Motivation Myelogenous N-isopropylacrylamide Oryctolagus cuniculus Oxidation-Reduction Patient-Focused Outcomes Patients Phagocytes Pharmaceutical Preparations Polyethylene Glycols Polymers Population Positioning Attribute Primary carcinoma of the liver cells Procedures Regulatory T-Lymphocyte Reporting Safety Solid Neoplasm Sulfides Suppressor-Effector T-Lymphocytes System TLR7 gene Techniques Technology Testing Therapeutic Embolization Therapeutic Intervention Tissues Up-Regulation Vaccination Vascular blood supply Water base biomaterial compatibility cancer cell cancer immunotherapy cancer therapy cytokine design ethylene glycol experience experimental study granulocyte high reward high risk image guided immunoregulation improved in vivo innovation iodixanol killings lymph flow macrophage monocyte nanocarrier nanomaterials neoplastic cell novel novel strategies novel therapeutics oncology pre-clinical pressure prevent propylene public health relevance response targeted delivery tool tumor tumor growth tumor microenvironment tumor progression

项目摘要

DESCRIPTION (provided by applicant): Inoperable cancers, such as most cases of hepatocellular carcinoma, remain a significant clinical challenge; therefore, novel therapies are required to improve the patient's outcome. Although immunotherapy in the form of cancer vaccination has shown some efficacy in generating the antigen-specific cellular responses required to prevent, control and reverse tumor growth, these responses are often ineffective due to the suppressive mechanisms present within the tumor. Therapeutic intervention through immune suppression has been shown to improve cancer immunotherapy; however, severe side effects, such as autoimmunity, often occur during systemic administration. We hypothesize that localized and persistent targeting of immunomodulators to the tumor microenvironment via a bioengineered immunostimulatory depot delivered by percutaneous intervention will reverse intratumoral immune suppression and lead to a halt in tumor progression and/or regression. To test this hypothesis, the overall goal of this proposal is to achieve localized and sustained delivery of a pro-apoptotic drug and an immunostimulatory drug to intratumoral inflammatory cell populations using a novel technique we refer to as Transarterial Immunomodulatory Embolization (TIE). Similar to transarterial chemoembolization (TACE), TIE is an image-guided, minimally-invasive surgical procedure that could potentially be used to treat malignant inoperable lesions in the liver. Unlike TACE, where improper embolization via microparticles can reduce blood supply to normal liver tissue, TIE can be easily reversed and the procedure repeated due to the use of a thermoreversible citrate-based polymer as the delivery and embolization vehicle. The ability to reverse the embolization means that many more patients would be eligible for the procedure. The specific aims are to: 1) Fabricate and characterize a thermoreversible radiopaque embolic agent that can efficiently entrap and slowly deliver inflammatory immunostimulants via release of redox-sensitive nanocarriers, and 2) Assess whether the TIE system developed in Specific Aim 1 will activate resident tumor immune cells and inhibit tumor growth in a rabbit liver cancer model. The proposed experiments will allow us to develop and evaluate an innovative approach to treat tumors and lay the foundation for novel tools that could potentially be used to help elucidate mechanisms of immunomodulation by locally targeting the tumor microenvironment via percutaneous intervention.