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

• 批准号: 10024878
• 负责人: Zachary Scott Morris
• 金额: $ 249.09万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 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/10024878
• 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; In Situ; 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 vivo; multidisciplinary; neoantigens; neoplastic cell; next generation; novel; programs; receptor; research clinical testing; research facility; response; success; tumor; tumor microenvironment; vector

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.

项目概要——总体 该计划项目拨款将建立完全综合的跨学科研究和核心计划 对于两个人之间复杂的相互作用有一个基本的理解所必需的设施 癌症治疗中快速新兴的领域：1）靶向放射性核素治疗（TRT）和2）免疫治疗。我们的 总体目标是对免疫调节能力有详细的机制理解 TRT 药物的研究，并评估和比较这些药物引发协同治疗的能力 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 制剂使用临床相关的小鼠肿瘤模型和同伴犬科动物在体内提供辐射 自发患上癌症。我们将确定每种放射性核素的精确剂量测定，TRT 载体模型和肿瘤模型。这将有助于研究剂量、剂量率和剂量范围依赖性影响 宿主免疫系统、肿瘤浸润免疫细胞、肿瘤微环境中细胞因子的表达、 肿瘤细胞的免疫敏感性、免疫抑制机制以及抗原的产生 特异性适应性免疫。我们将通过测试广泛的结果来确定这些影响的功能后果 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，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：用于剂量测定引导免疫调节的新型 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：TRT与局部原位疫苗相结合，克服肿瘤中的免疫抑制 微环境和增强 T 细胞反应 项目4：用肿瘤特异性疫苗进行TRT刺激和扩大T细胞活化 这些高度集成的项目不仅将受益于彼此产生的方法和发现， 但他们也将直接受益于四个重要核心设施的专业知识和服务：1) 先进 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。健全的机构设施是对这些的补充 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 调动这些资源以实现我们提出的目标需要广泛的专业知识。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的领导， 宝贵的行业合作以及外部顾问委员会的专业知识。由于即时和 我们的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。