Administrative-Core-001

项目总结(同CA250972) 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 使用临床相关的小鼠肿瘤模型和伴犬进行体内放射治疗的TRT试剂 自发地患上癌症的人。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、剂量率和剂量范围相关的研究 对宿主免疫系统、肿瘤浸润性免疫细胞、肿瘤细胞因子表达的影响 微环境，肿瘤细胞的免疫敏感性，免疫抑制机制，以及 抗原特异性获得性免疫的研究进展。我们将确定这些项目的功能后果 通过检验广泛的假设，通过调节肿瘤的免疫耐受性和功能 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 这是在以下计划项目中：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 微环境和增强T细胞反应，项目4：TRT与肿瘤特异性疫苗刺激和 扩大T细胞活化。这些高度整合的项目不仅将受益于方法和发现 产生于彼此，但他们也将直接受益于四个必不可少的专业知识和服务 核心设施：1)先进成像和剂量测定核心(AIDC)，2)放射制药和放射化学 核心(RPRC)，3)生物统计和生物信息学核心(BBC)，以及4)行政核心。补充这些 都是健全的制度设施，将使我们能够成功完成拟议的研究。我们的 多学科团队汇集了动员这些资源所需的广泛专业知识，以追求 建议的目标。这些努力将进一步受益于强有力的机构匹配支持、 强大的内部咨询委员会、宝贵的行业协作以及外部咨询的专业知识 冲浪板。由于我们的研究结果具有直接和广泛的临床转化潜力，这些研究 预示着有机会改善任何肿瘤科患者的治疗，无论癌症类型、肿瘤 地点、疾病负担或患者年龄。

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.