Administrative-Core-001

行政核心-001

• 批准号: 10707579
• 负责人: Zachary Scott Morris
• 金额: $ 7万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707579
• 关键词: Administrative; Core; 001

PROJECT SUMMARY (same as CA250972) This Program Project grant will establish the fully integrated interdisciplinary programs of research and core facilities that are necessary to develop a fundamental understanding of the complex interplay between two rapidly emerging fields in cancer therapy: 1) targeted radionuclide therapy (TRT) and 2) immunotherapy. Our overarching objectives are to develop a detailed mechanistic understanding of the immunomodulatory capacity of TRT agents and to evaluate and compare the ability of these agents to elicit cooperative therapeutic interactions in combination with immunotherapies. To achieve this, we will employ a representative variety of TRT agents to deliver radiation in vivo using clinically relevant murine tumor models and companion canines that have spontaneously developed cancers. We will determine the precise dosimetry for each radionuclide-, TRT vector-, and tumor model. This will facilitate studies of dose-, dose-rate-, and dose-range-dependent effects on the host immune system, tumor infiltrating immune cells, cytokine expression in the tumor microenvironment, immune susceptibility of tumor cells, mechanisms of immune suppression, and the development of antigenspecific adaptive immunity. We will determine the functional consequences of these effects by testing the broad hypothesis that, by modulating tumor immune tolerance and functional immunogenicity at all tumor sites, TRT will increase response to certain cancer immunotherapies. We will test this in the following Program Projects: Project 1: Novel TRTs for Dosimetry-Guided Immunomodulation, Project 2: TRT to enhance tumor cell immune susceptibility and response to immune checkpoint inhibitors, Project 3: Combining TRT with a localized in situ vaccine to overcome immune suppression in the tumor microenvironment and augment T cell responses, Project 4: TRT with tumor-specific vaccine to stimulate and expand T-cell activation. These highly integrated projects will not only benefit from the methods and findings generated in one another, but they also will directly benefit from the expertise and service of four essential Core Facilities: 1) Advanced imaging and dosimetry core (AIDC), 2) Radiopharmaceutical and radiochemistry core (RPRC), 3) Biostatistics and bioinformatics core (BBC), and 4) Administrative core. Complementing these are robust institutional facilities that will enable successful completion of our proposed studies. Our multidisciplinary team brings together the broad expertise needed to mobilize these resources in pursuit of our proposed objectives. These efforts will further benefit from robust institutional matching support, leadership of a strong Internal Advisory Committee, invaluable Industry collaborations, and expertise of an External Advisory Board. Because of the immediate and broad potential for clinical translation of our results, these studies portend an opportunity to improve the treatment of any oncology patient, regardless of cancer type, tumor location, burden of disease, or patient age.

项目摘要（与CA250972相同） 该计划项目赠款将建立完整整合的研究和核心的跨学科计划 对两者之间的复杂相互作用的基本了解所需的设施 癌症治疗中快速新兴领域：1）靶向放射性核素治疗（TRT）和2）免疫疗法。我们的 总体目标是对免疫调节能力有详细的机械理解 TRT代理并评估和比较这些药物引起合作治疗的能力 相互作用与免疫疗法结合使用。为了实现这一目标，我们将采用代表性的多种多样 TRT剂使用临床相关的鼠肿瘤模型和伴侣犬在体内提供辐射 自发发展的癌症。我们将确定每个放射性核素的精确剂量测定法 TRT矢量和肿瘤模型。这将促进剂量，剂量率和剂量范围依赖性的研究 对宿主免疫系统，肿瘤浸润免疫细胞的影响，肿瘤中细胞因子的表达 微环境，肿瘤细胞的免疫敏感性，免疫抑制机制以及 抗原特异性适应性免疫的发展。我们将确定这些功能后果 通过检验广泛的假设，即通过调节肿瘤免疫耐受性和功能 在所有肿瘤部位的免疫原性，TRT将增加对某些癌症免疫疗法的反应。我们将测试 这在以下程序项目中：项目1：用于剂量学引导的免疫调节的新型TRT， 项目2：TRT增强肿瘤细胞免疫易感性和对免疫检查点抑制剂的反应， 项目3：将TRT与局部原位疫苗结合起来，以克服肿瘤中的免疫抑制 微环境和增强T细胞反应，项目4：带有肿瘤特异性疫苗的TRT刺激和 扩展T细胞激活。这些高度集成的项目不仅将从方法和发现中受益 彼此产生，但它们也将直接从四个基本的专业知识和服务中受益 核心设施：1）高级成像和剂量学核心（AIDC），2）放射性药物和放射化学 核心（RPRC），3）生物统计学和生物信息学核心（BBC）和4）行政核心。补充这些 是强大的机构设施，可以成功完成我们拟议的研究。我们的 多学科团队汇集了动员这些资源所需的广泛专业知识，以追求我们 提出的目标。这些努力将进一步受益于强大的机构匹配支持， 强大的内部咨询委员会，宝贵的行业合作以及外部咨询的专业知识 木板。由于我们的结果的临床翻译具有直接和广泛的潜力，这些研究 预示着改善任何肿瘤患者治疗的机会，无论癌症类型如何 位置，疾病负担或患者年龄。