Molecular Targeted Radionuclide Therapy for Tumor Immunomodulation and Enhancing Immunotherapy Response

项目总结--总体 该计划项目赠款将建立完全整合的跨学科研究和核心计划 对于从根本上理解两者之间复杂的相互作用所必需的设施 肿瘤治疗中迅速崛起的领域：1)靶向放射性核素治疗(TRT)和2)免疫治疗。我们的 首要目标是发展对免疫调节能力的详细的机械理解。 并评估和比较这些药物诱导合作治疗的能力 与免疫疗法相结合的相互作用。为了实现这一目标，我们将采用具有代表性的各种 TRT试剂在体内使用临床相关的小鼠肿瘤模型和伴犬进行放射治疗 会自发地患上癌症。我们将确定每个放射性核素的精确剂量学-，TRT 载体和肿瘤模型。这将促进剂量、剂量率和剂量范围依赖效应的研究。 宿主免疫系统，肿瘤浸润性免疫细胞，肿瘤微环境中细胞因子的表达， 肿瘤细胞的免疫敏感性、免疫抑制机制及抗原的研究进展 特异性适应性免疫。我们将通过测试广泛的 假设，通过调节肿瘤免疫耐受和所有肿瘤部位的功能免疫原性，TRT 会增加对某些癌症免疫疗法的反应。我们将在以下计划项目中对此进行测试： 项目1：用于剂量学指导的免疫调节的新型TRT 项目2：TRT增强肿瘤细胞免疫敏感性和对免疫检查点抑制剂的反应 项目3：将TRT与局部原位疫苗相结合以克服肿瘤中的免疫抑制 微环境与增强T细胞反应 项目4：使用肿瘤特异性疫苗进行TRT以刺激和扩大T细胞激活 这些高度整合的项目不仅将受益于彼此产生的方法和结果， 但他们还将直接受益于四个基本核心设施的专业知识和服务：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)，以及4)管理核心。与之相辅相成的是健全的制度设施。 这将使我们能够成功完成拟议的研究。我们的多学科团队汇集了 为实现我们提出的目标而调动这些资源所需的广泛专业知识。这些努力将 进一步受益于强有力的机构配对支持、强大的内部咨询委员会的领导， 宝贵的行业合作，以及外部咨询委员会的专业知识。因为迫在眉睫 我们的结果具有广阔的临床转化潜力，这些研究预示着改善治疗的机会 任何肿瘤患者，无论癌症类型、肿瘤部位、疾病负担或患者年龄。

PROJECT SUMMARY – OVERALL 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 antigen- specific 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.