Molecular Targeted Radionuclide Therapy for Tumor Immunomodulation and Enhancing Immunotherapy Response

项目概要-总体 该计划项目赠款将建立研究和核心的完全整合的跨学科计划 这些设施是必要的，以发展一个基本的理解之间的复杂的相互作用， 在癌症治疗中迅速出现的领域：1）靶向放射性核素治疗（TRT）和2）免疫治疗。我们 总体目标是对免疫调节能力有一个详细的机制性理解， 并评价和比较这些药物引起合作治疗的能力 与免疫疗法的相互作用。为了实现这一目标，我们将采用具有代表性的各种 使用临床相关的鼠肿瘤模型和伴侣犬在体内递送辐射的TRT剂， 会自发地患上癌症我们将确定每种放射性核素的精确剂量-TRT 载体和肿瘤模型。这将有助于研究剂量依赖性、剂量率依赖性和剂量范围依赖性效应， 宿主免疫系统，肿瘤浸润免疫细胞，肿瘤微环境中的细胞因子表达， 肿瘤细胞的免疫易感性，免疫抑制机制，以及抗原- 特异性适应性免疫我们将通过测试广泛的 假设TRT通过调节所有肿瘤部位的肿瘤免疫耐受和功能免疫原性， 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增强肿瘤细胞免疫易感性和对免疫检查点抑制剂的反应 项目3：TRT与局部原位疫苗结合，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 这些高度综合的项目不仅将受益于彼此产生的方法和结果， 但他们也将直接受益于四个基本核心设施的专业知识和服务： 成像和剂量测定核心（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）行政核心。作为补充， 使我们能够顺利完成拟议的研究。我们的多学科团队汇集了 需要广泛的专门知识来调动这些资源，以实现我们提出的目标。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的领导， 宝贵的行业合作和外部咨询委员会的专业知识。由于直接和 我们的研究结果具有广泛的临床转化潜力，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、肿瘤位置、疾病负担或患者年龄如何。

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.