Molecular Targeted Radionuclide Therapy to Enhance Tumor Cell Susceptibility and Response to Immune Checkpoint Inhibition

分子靶向放射性核素治疗增强肿瘤细胞对免疫检查点抑制的敏感性和反应

• 批准号: 10263247
• 负责人: Zachary Scott Morris
• 金额: $ 39.2万
• 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/10263247
• 关键词: 90Y; Abbreviations; Affect; Alpha Particles; Antigen Presentation; Antigens; Antitumor Response; Beta Particle; Cancer Patient; Cells; Clinical Research; Clinical Sensitivity; Clinical Trials; Clonal Expansion; Controlled Study; Diagnostic radiologic examination; Disease; Disseminated Malignant Neoplasm; Dose; Dose-Rate; Electrons; External Beam Radiation Therapy; Feedback; Gamma Rays; Gene Expression Profiling; Generations; Genetically Engineered Mouse; Goals; Half-Life; Image; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunologic Memory; Immunologics; Immunotherapy; Individual; Inflammation; Interferon Type I; Interferons; Linear Energy Transfer; Location; Malignant neoplasm of prostate; Measurement; Mediating; Modeling; Molecular Target; Monitor; Mus; Neuroblastoma; Organism; Outcome; Pathway interactions; Patients; Predisposition; Production; Radiation; Radiation therapy; Radioactive; Radioisotopes; Radionuclide therapy; Regulatory T-Lymphocyte; Scanning; Site; Stimulator of Interferon Genes; T cell clonality; T cell response; T-cell receptor repertoire; TREX1 gene; Testing; Therapeutic; Three Prime Repair Exonuclease 1; Toxic effect; Translations; Treatment Protocols; Tumor Antigens; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; Variant; Veins; Virus Diseases; Whole-Body Irradiation; anti-CTLA4; anti-PD-1; anti-tumor immune response; cancer therapy; checkpoint inhibition; clinically relevant; ds-DNA; effectiveness testing; follow-up; immunogenic cell death; immunoregulation; improved; in situ vaccine; in vivo; insight; melanoma; multidisciplinary; neoplastic cell; next generation; preclinical study; prospective; research clinical testing; response; targeted treatment; tumor; tumor microenvironment; vector

PROJECT SUMMARY – PROJECT 2 In a project that builds upon the ongoing collaborative progress of our multidisciplinary team, we will systematically evaluate mechanisms of cooperative interaction and optimize the potency of treatment regimens that combine targeted radionuclide therapies (TRT) with immune checkpoint inhibition (ICI; e.g. anti-PD- 1, anti-CTLA-4) to enhance the anti-tumor immune response against metastatic cancers. Moderate dose (8-12 Gy) external beam radiation therapy (EBRT) is capable of eliciting an in situ vaccine effect, converting the targeted tumor into a nidus for enhanced tumor antigen recognition. In preclinical and clinical studies, this results in diversification of the T cell receptor (TCR) repertoire. Consequently, in preclinical studies, EBRT improves the response to ICIs. This is at least in part dependent upon the capacity of EBRT to activate a type I interferon (IFN) response in radiated tumor cells. However, clinical studies have not yet conclusively demonstrated a benefit from combining EBRT with ICIs, and even in studies that suggest a benefit it is clear that more is needed if we aim to develop an effective approach to eradicating metastatic disease for all cancer patients. In pursuit of such a goal, we now propose to evaluate a next generation strategy to leveraging the capacity of radiation to enhance response to ICIs by using TRTs to deliver radiation to all tumor sites in settings of metastatic disease. To begin testing this approach, we will compare the relative capacities of different TRT agents to 1) activate a type I IFN response in tumor cells, 2) augment response to ICIs, and 3) increase the diversity and clonality of the TCR repertoire among tumor infiltrating lymphocytes. We hypothesize that TRT will enhance the rate and depth of response to ICIs and that this will correlated with effects on the TCR repertoire that are dependent on the ability of TRT to modulate tumor cell immune susceptibility by activating a type I IFN response. We expect that TRTs will also elicit immunogenic cell death, local inflammation, and temporary depletion of suppressive regulatory T cells (Tregs) from the tumor microenvironment (TME), and other Projects in this P01 will investigate those mechanisms further. Here, we will compare the relative effects of TRT radionuclides and vectors in order to develop a fundamental understanding of the interactions between these agents and anti-tumor immunity. In particular, we will evaluate the potential impacts of tumor size, type, and number as well as the type of radioactive decay products (e.g. α particle vs β particle vs γ-ray vs Auger electron), linear energy transfer (LET), dose, dose- rate and half-life, and dose range. We will also examine the potential impact of the TRT vector, specifically testing how changes in TRT distribution at the organism, tumor, and subcellular level affect anti-tumor immunity. The insights and treatment regimens developed in these studies should enable rapid translation to clinical testing in patients with any type of metastatic cancer while also launching a generation of follow-up basic and translational preclinical studies.

项目总结-项目2