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（由适用提供）：无法手术的癌症，例如大多数肝细胞癌病例，仍然是一个重大的临床挑战；因此，需要新的疗法来改善患者的结局。尽管以癌症疫苗形式的免疫疗法在产生预防，控制和逆转肿瘤生长所需的抗原特异性细胞反应方面表现出一定的有效性，但由于肿瘤中存在抑制性机制，这些反应通常是无效的。通过免疫抑制的治疗干预已被证明可以改善癌症免疫疗法。但是，严重的副作用，例如自身免疫性，通常在全身给药期间发生。我们假设通过经皮干预提供的生物工程的免疫刺激性仓库将免疫调节剂局部靶向肿瘤显微环境，将逆转肿瘤内免疫抑制，并导致肿瘤进展和/或或/或或/或回归。为了检验这一假设，该提案的总体目标是实现促凋亡药物的局部和持续递送，并使用我们称为跨性别免疫调节性栓塞（TIE）的新技术，将免疫刺激性药物和一种免疫刺激性药物传递到肿瘤内炎症细胞种群中。与跨细胞化学栓塞（TACE）相似，TIE是一种图像引导，微创的手术程序，有可能用于治疗肝脏中的恶性损伤。与TACE不同的是，通过微粒栓塞栓塞不当会减少对正常肝组织的血液供应，因此很容易逆转扎带，并且由于使用了可耐柠檬酸盐的聚合物作为递送和栓塞车而导致的过程重复。扭转栓塞的能力意味着更多的患者有资格参加该手术。 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 residents tumor immunocells cells and inhibit tumor growth in a rabbit liver cancer model.提出的实验将使我们能够开发和评估一种治疗肿瘤的创新方法，并为新型工具奠定了基础，这些工具可以通过经皮干预来局部靶向肿瘤微环境，从而有可能用于帮助阐明免疫调节机制。