Project 3: Combining Radiotherapy and Nanotechnology for Immunotherapy

项目3：放射治疗与纳米技术相结合进行免疫治疗

• 批准号: 9546627
• 负责人: Andrew Zhuang Wang
• 金额: $ 23.92万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9546627
• 关键词: Abscopal effect; Agonist; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Antigens; Artificial nanoparticles; Bilateral; CCNE1 gene; Cancer Patient; Cells; Charge; Chemistry; Clinical; Collaborations; Contralateral; Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Development; Discipline; Disease; Disease model; Encapsulated; Engineering; Exposure to; Goals; Hydrophobic Surfaces; Immune; Immune response; Immune system; Immunologic Adjuvants; Immunomodulators; Immunotherapeutic agent; Immunotherapy; Ink; Malignant Neoplasms; Matrix Metalloproteinase Inhibitor; Modeling; Mus; Nanotechnology; Patients; Property; Radiation therapy; Regimen; Regulatory Pathway; Research; SLEB2 gene; Scheme; Surface; Surface Properties; Translating; Treatment Efficacy; Tumor Antigens; Tyrosine; Work; antigen binding; biodegradable polymer; biomaterial compatibility; cancer immunotherapy; cancer therapy; improved; in vivo; in vivo evaluation; inhibitor/antagonist; innovation; interest; irradiation; melanoma; mouse model; nano; nanoparticle; neoplastic cell; novel; novel strategies; pre-clinical; response; success; treatment effect; tumor; tumor growth; tumor microenvironment

Project 3 Abstract Immunotherapy has emerged as an exciting new strategy in cancer treatment. The development of antibodies that can block negative immune regulatory pathways have resulted in clinical improvements in cancer patients that was not seen previously. Because of this success, there has been strong research and clinical interest in developing strategies to further improve cancer immunotherapy. One key strategy has been to utilize radiotherapy to enhance immunotherapy effects. Radiotherapy is thought to increase the antigen exposure to the immune system. There is also growing preclinical data demonstrating that nanoparticles (NPs) can enhance immunotherapy by improving antigen presentation. We hypothesize that we can engineer NPs that can capture the antigens released by radiotherapy and such NPs can enhance the effects of immunotherapy. We have preliminary data demonstrating that NPs can indeed capture tumor antigens released from radiotherapy. We have termed these NPs antigen-capturing NPs or AC- NP. Using a mouse model of melanoma, we have demonstrated AC-NPs, when given in conjunction with αCTLA-4 antibody, can improve immunotherapy efficacy. The therapeutic efficacy of AC-NPs are dependent on the NPs' surface properties. We have also demonstrated that AC-NPs, when injected into tumors after radiotherapy, can generate systemic immune response against tumor cells in mice. The central goal of this application is to develop NPs that can effectively capture tumor antigens released by radiotherapy and evaluate these NPs in cancer immunotherapy. Our application has 3 specific aims: Aim 1: To optimize the size and surface chemistry of AC-NPs for capturing tumor antigen released from radiotherapy Aim 2: To determine whether AC-NPs can enhance the abscopal effect by radiotherapy. Aim 3: To determine whether AC-NPs' efficacy in enhancing the radiation therapy abscopal effect can be further improved by the addition of tumor microenvironment modifiers. To accomplish this goal, we plan to engineer biocompatible and biodegradable NPs with various size and surface properties. Melanoma will be used as a model disease for our work since it is a disease that has clearly benefited from immunotherapy. Furthermore, there are well-established mouse melanoma models for immunotherapy and extensive research using these tumor models. Our application combines concepts from several disciplines: nanotechnology, immune therapy and radiotherapy, in developing a novel strategy to improve cancer immunotherapy. Our work can increase the response rates of cancer immunotherapy which will directly translate into increased cure and survival in patients. While our work is focused on melanoma as a model, our results may be broadly applied to other cancers.

项目3摘要 免疫疗法已成为癌症治疗中令人兴奋的新策略。 可以阻断负性免疫调节途径，从而改善癌症患者的临床症状 由于这一成功，人们对它产生了浓厚的研究和临床兴趣。 制定进一步改善癌症免疫治疗的策略之一是利用。 放射治疗可增强免疫治疗效果。放射治疗被认为可增加抗原暴露。 越来越多的临床前数据表明纳米颗粒 (NP) 可以 通过改善抗原呈递来增强免疫治疗。 我们进化到可以设计纳米颗粒来捕获放疗等释放的抗原 我们有初步数据证明纳米颗粒确实可以增强免疫治疗的效果。 捕获放疗释放的肿瘤抗原，我们将这些 NP 称为抗原捕获 NP 或 AC-。 NP。使用黑色素瘤小鼠模型，我们已经证明了 AC-NP 与 αCTLA-4抗体，可以提高免疫治疗效果，AC-NPs的治疗效果有依赖性。 我们还证明了AC-NPs注射到肿瘤后的表面特性。 放射治疗可以在小鼠体内产生针对肿瘤细胞的全身免疫反应。 该应用的中心目标是开发能够有效捕获肿瘤细胞释放的肿瘤抗原的纳米颗粒。 我们的应用有 3 个具体目标： 目标 1：优化 AC-NP 的尺寸和表面化学，以捕获从 放射治疗 目标 2：确定 AC-NPs 是否可以增强放射治疗的远隔效应。 目标 3：确定 AC-NPs 在增强放射治疗远隔效应方面的功效是否可以 通过添加肿瘤微环境调节剂进一步改善。 为了实现这一目标，我们计划设计具有不同尺寸和尺寸的生物相容性和可生物降解的纳米颗粒。 黑色素瘤将用作我们工作的模型疾病，因为它是一种具有以下特征的疾病： 此外，已有成熟的小鼠黑色素瘤模型。 使用这些肿瘤模型进行免疫疗法和广泛的研究。 我们的应用程序结合了多个学科的概念：纳米技术、免疫治疗和 放射治疗，开发一种新的策略来改善癌症免疫治疗。 癌症免疫疗法的反应率将直接转化为提高治愈率和生存率 虽然我们的工作重点是黑色素瘤模型，但我们的结果可能广泛应用于其他患者。 癌症。