Molecular Targeted Radionuclide Therapy for Tumor Immunomodulation and Enhancing Immunotherapy Response

分子靶向放射性核素治疗肿瘤免疫调节和增强免疫治疗反应

基本信息

批准号：
10263244
负责人：
Zachary Scott Morris
金额：
$ 250.85万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-14 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10263244
关键词：
Advisory Committees Age Antigens Antitumor Response Award Bioinformatics Biometry Cancer Patient Canis familiaris Categories Cells Clonal Expansion Companions Complement Complex Core Facility Data Development Disease Disseminated Malignant Neoplasm Distant Dose Dose-Rate Ensure External Beam Radiation Therapy FDA approved Funding Mechanisms Image Immune Immune Tolerance Immune checkpoint inhibitor Immune system Immunologics Immunosuppression Immunotherapy Industry Collaboration Interferon Type I Investigational Therapies Knowledge Leadership Ligands Location Low Dose Radiation Malignant Neoplasms Mediating Methods Microscopic Modality Modeling Molecular Target Mus Mutation Oncology Patients Pharmaceutical Preparations Predisposition Process Program Research Project Grants Protocols documentation Radiation Radiation therapy Radiochemistry Radioisotopes Radiolabeled Radionuclide therapy Radiopharmaceuticals Regimen Research Resources Role Safety Services Site T cell response T-Cell Activation T-Lymphocyte Testing Therapeutic Toxic effect Tumor Immunity Tumor-infiltrating immune cells Vaccines Veins Whole-Body Irradiation adaptive immunity anti-tumor immune response antigen-specific T cells burden of illness cancer immunotherapy cancer therapy cancer type clinical translation clinically relevant curative treatments cytokine dosimetry exhaustion experience immunogenicity immunoregulation improved in situ vaccine in vivo multidisciplinary neoantigens neoplastic cell next generation novel programs receptor research clinical testing research facility response success tumor tumor microenvironment vector

项目摘要

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.

项目摘要 - 总体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）靶向放射线疗法（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使用临床相关的鼠肿瘤模型和伴侣犬在体内提供辐射的TRT剂有赞助的癌症。我们将确定每个放射线的精确剂量测定法载体和肿瘤模型。这将促进研究剂量，剂量率和剂量范围依赖性对宿主免疫系统，肿瘤浸润免疫细胞，肿瘤微环境中的细胞因子表达，肿瘤细胞的免疫敏感性，免疫抑制机制以及抗原的发展特定的自适应免疫。我们将通过测试广泛来确定这些效果的功能后果假设通过调节所有肿瘤部位的肿瘤免疫耐受性和功能性免疫原性将增加对某些癌症免疫疗法的反应。我们将在以下程序项目中进行测试：项目1：剂量指导的免疫调节的新型TRT 项目2：TRT增强肿瘤细胞免疫抑制性和对免疫检查抑制剂的反应项目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以刺激和扩展T细胞激活这些高度集成的项目不仅将从彼此产生的方法和发现中受益，但是它们还将直接从四个基本核心设施的专业知识和服务中受益：1）高级成像和剂量测定核（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这将使我们提出的研究成功完成。我们的多学科团队将为了追求我们提出的目标，需要动员这些资源所需的广泛专业知识。这些努力会强大的机构匹配支持，强大内部咨询委员会的领导宝贵的行业合作和外部顾问委员会的专业知识。因为直接和这些研究的临床翻译的广泛潜力预示了改善治疗的机会任何肿瘤患者，无论癌症类型，肿瘤的位置，疾病燃烧或患者年龄如何。