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 免疫疗法已经成为癌症治疗中一种令人兴奋的新策略。抗体的研究进展 可以阻断负免疫调节通路的药物可以改善癌症患者的临床症状。 这是以前没有见过的。由于这一成功，已经有了强烈的研究和临床兴趣 制定进一步改进癌症免疫治疗的策略。一项关键的战略是利用 放射治疗可增强免疫治疗效果。放射治疗被认为增加了接触抗原的机会 免疫系统。也有越来越多的临床前数据表明，纳米颗粒(NPs)可以 通过改善抗原提呈来加强免疫治疗。 我们假设我们可以设计出能够捕获放射治疗释放的抗原的NPs等等 NPS可增强免疫治疗的效果。我们有初步数据表明，NPs确实可以 捕获放射治疗释放的肿瘤抗原。我们称这些NPs为捕获抗原的NPs或AC- NP。使用黑色素瘤的小鼠模型，我们已经展示了AC-NPs，当与 αCTLA-4抗体，可提高免疫治疗疗效。AC-NPs的治疗效果是依赖的 关于NPs的表面性质。我们还证明了AC-NPs在注射到肿瘤后 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。 这项应用的中心目标是开发能够有效捕获由 并评价这些纳米粒子在癌症免疫治疗中的应用。我们的应用程序有3个具体目标： 目的1：优化AC-NPs的大小和表面化学，以捕获肿瘤释放的抗原 放射治疗 目的2：探讨AC-NPs能否增强放射治疗的非靶区效应。 目的3：确定AC-NPs是否能增强放射治疗的非靶向性效应 通过添加肿瘤微环境改良剂进一步改善。 为了实现这一目标，我们计划设计出各种大小和可生物降解的生物兼容和可生物降解的纳米粒子 曲面特性。黑色素瘤将被用作我们工作的模型疾病，因为它是一种 显然受益于免疫疗法。此外，已经有成熟的小鼠黑色素瘤模型用于 利用这些肿瘤模型进行免疫治疗和广泛的研究。 我们的应用结合了几个学科的概念：纳米技术、免疫疗法和 放射治疗，在开发一种新的战略，以改善癌症免疫治疗。我们的工作可以增加 癌症免疫治疗的应答率将直接转化为提高治愈率和存活率 病人。虽然我们的工作集中在黑色素瘤作为一个模型，但我们的结果可能会广泛应用于其他 癌症。