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.

项目概要-项目2 在一个建立在我们多学科团队正在进行的合作进展的项目中，我们将 系统地评估合作相互作用的机制，优化治疗方案的效力 将联合收割机靶向放射性核素疗法（TRT）与免疫检查点抑制（ICI;例如抗PD-1）结合， 1，抗CTLA-4）以增强针对转移性癌症的抗肿瘤免疫应答。中等剂量 (8-12戈伊）外照射放射治疗（EBRT）能够引发原位疫苗效应，将 靶向肿瘤进入病灶以增强肿瘤抗原识别。在临床前和临床研究中， T细胞受体（TCR）库的多样化。因此，在临床前研究中，EBRT改善了 对ICI的回应这至少部分取决于EBRT激活I型干扰素（IFN）的能力。 放射性肿瘤细胞的反应。然而，临床研究尚未最终证明 将EBRT与ICI相结合，即使在研究中表明有益，但如果我们的目标是 开发一种有效的方法来根除所有癌症患者的转移性疾病。为了实现这一目标， 我们现在建议评估下一代战略，以利用辐射能力， 通过使用TRT向转移性疾病背景下的所有肿瘤部位提供放射治疗来响应ICI。开始 测试这种方法，我们将比较不同的TRT剂的相对能力：1）激活I型IFN 2）增强对ICI的应答，和3）增加TCR的多样性和克隆性 肿瘤浸润性淋巴细胞之间的库。我们假设TRT将提高 对ICI的反应，这将与对TCR库的影响相关，TCR库依赖于免疫抑制剂的能力。 TRT通过激活I型IFN应答来调节肿瘤细胞免疫易感性。我们希望TRT 也会引起免疫原性细胞死亡、局部炎症和抑制性调节性T细胞的暂时耗竭。 肿瘤微环境（TME）中的细胞（TME），本P01中的其他项目将研究这些 机制进一步。在这里，我们将比较TRT放射性核素和载体的相对影响， 发展这些代理和抗肿瘤免疫之间的相互作用的基本理解。在 特别是，我们将评估肿瘤大小，类型和数量以及放射性类型的潜在影响。 衰变产物（例如α粒子vs β粒子vs γ射线vs俄歇电子）、线性能量转移（LET）、剂量、剂量- 速率和半衰期以及剂量范围。我们还将研究TRT载体的潜在影响，特别是测试 TRT在机体、肿瘤和亚细胞水平分布的变化如何影响抗肿瘤免疫。的 在这些研究中开发的见解和治疗方案应能够快速转化为临床 在患有任何类型的转移性癌症的患者中进行测试，同时还启动了一代随访， 基础和转化临床前研究。