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: 10672926
• 负责人: Zachary Scott Morris
• 金额: $ 38.43万
• 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/10672926
• 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; Cytoplasm; 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; novel therapeutic intervention; preclinical study; prospective; radiological imaging; 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.

项目摘要 - 项目2 在一个基于我们多学科团队持续的合作进展的项目中，我们将 系统地评估合作互动的机制并优化治疗方案的效力 与免疫抑制（ICI;例如抗PD- 1，抗CTLA-4），以增强针对转移性癌症的抗肿瘤免疫反应。中等剂量 （8-12 Gy）外束辐射疗法（EBRT）能够引起原位疫苗作用，转化 靶向肿瘤进入Nidus，以增强肿瘤抗原识别。在临床前和临床研究中，这一结果 T细胞受体（TCR）曲目多样化。因此，在临床前研究中，EBRT改善了 对ICIS的反应。这至少部分取决于EBRT激活I型干扰素的能力（IFN） 放射性肿瘤细胞的反应。但是，临床研究尚未最终证明 将EBRT与ICI相结合，甚至在表明受益的研究中，很明显，如果我们的目标是 开发一种有效的方法来消除所有癌症患者的转移性疾病。为了实现这样一个目标， 现在，我们建议评估下一代策略，以利用辐射的能力增强 通过使用TRT在转移性疾病环境中向所有肿瘤部位提供辐射对ICI的反应。开始 测试这种方法，我们将比较不同TRT剂的相对能力与1）激活I型IFN 肿瘤细胞的反应，2）增强对ICI的反应，3）增加TCR的多样性和克隆性 肿瘤浸润淋巴细胞之间的曲目。我们假设TRT将提高速率和深度 对ICI的响应，这将与对TCR曲目的影响有关，这取决于能力 通过激活I型IFN反应来调节肿瘤细胞免疫易感性。我们期望这是TRT 还将引起免疫原性死亡，局部炎症以及抑制性调节t的暂时耗竭 来自肿瘤微环境（TME）的细胞（Tregs），该P01中的其他项目将研究这些细胞（TME） 进一步的机制。在这里，我们将比较trt radiuclides和向量的相对效果，以便 对这些药物与抗肿瘤免疫之间的相互作用有基本的了解。在 特别是，我们将评估肿瘤大小，类型和数字的潜在影响以及放射性的类型 衰减产物（例如α粒子与β粒子与γ射线相对于螺旋钻电子），线性能传递（LET），剂量，剂量 - 速率和半衰期和剂量范围。我们还将检查TRT矢量的潜在影响，专门测试 生物体，肿瘤和亚细胞水平的TRT分布的变化如何影响抗肿瘤免疫。这 这些研究中成立的见解和治疗方案应能够快速转化为临床 对任何类型的转移性癌症患者进行测试，同时也开始一代随访 基础和翻译的临床前研究。