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

• 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
• 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

 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.

 描述（由申请人证明）：无法手术的癌症，例如大多数肝细胞癌的Casse，对患者的结局需要新颖的疗法，以产生抗原特异性的细胞对患者的抗原症状。治疗性抑制作用已造成癌症，例如，诸如自身免疫性的严重副作用在全身给药期间发生。导致肿瘤进展和或回归。 TACE），是一种图像填充的，微创的外科手术，可能会用于肝脏中的不可能的无法手术的病变，与TACE不同，妓女通过微粒可以减少Bloce血液供应的肝脏。逆转到to t to t to t to t s someaoas扭转栓塞的能力意味着更多的患者符合该过程的资格。可以通过释放氧化还原敏感的纳米载体细胞有效地捕集吞噬TS，并抑制兔肝癌模型中的肿瘤生长。通过经皮干预局部靶向肿瘤。