Brachytherapy to achieve in situ cancer vaccination

近距离放射治疗实现原位癌症疫苗接种

• 批准号: 10328489
• 负责人: Justin Charles Jagodinsky
• 金额: $ 4.15万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10328489
• 关键词: Antigens; Applications Grants; Brachytherapy; Cancer Burden; Catheters; Cells; Clinical; Data; Disease; Disease Progression; Disseminated Malignant Neoplasm; Dose; Goals; Heterogeneity; ICAM1 gene; IFNAR1 gene; Immune; Immune Targeting; Immune Tolerance; Immune checkpoint inhibitor; Immune response; Immunologic Markers; Immunologics; Immunotherapy; Implant; Infiltration; Intention; Interferon-beta; Knowledge; Laws; Ligands; Location; Malignant Neoplasms; Methods; Modality; Modeling; Mus; Mutation; Outcome; Pathway interactions; Patients; Positioning Attribute; Predisposition; Privatization; Proteins; Radiation; Radiation Dose Unit; Radiation therapy; Radioactive; Recurrence; Regimen; Regulatory T-Lymphocyte; Research Personnel; Role; Seeds; Site; Source; Surface; T-Lymphocyte; Techniques; Testing; Therapeutic; Time; Translations; Treatment Protocols; Tumor Antigens; Vascular Cell Adhesion Molecule-1; adaptive immune response; anti-PD-L1; anti-tumor immune response; cancer immunotherapy; cytokine; effector T cell; exhaust; exhaustion; experimental study; immune activation; immune checkpoint blockade; immunogenic; immunogenicity; immunoregulation; improved; in situ cancer vaccination; in situ vaccination; in situ vaccine; insight; mouse model; neoantigens; neoplastic cell; novel strategies; preclinical study; prevent; programmed cell death ligand 1; radiation delivery; radiation effect; receptor; research clinical testing; response; success; synergism; tool; treatment strategy; tumor; tumor microenvironment; tumor-immune system interactions

Project Summary/Abstract We aim to improve the cure rates for metastatic cancers. To achieve this we propose a combined modality approach to stimulate and diversify an endogenous anti-tumor immune response capable of recognizing and destroying metastatic cancers in a manner that will prevent recurrence and enable long-term cancer free survival. Our intention is to develop a strategy that will overcome current challenges that limit the role of immunotherapy. Immune checkpoint inhibitors (ICI; e.g. anti-PD-L1), are a class of immunotherapies that modulate immune tolerance of a tumor by blocking specific inhibitory receptor-ligand interactions on the surface of T cells and thereby overcoming T cell inhibition or exhaustion. In patients with immunologically “hot” tumors, characterized by a pre-existing but exhausted anti-tumor immune response, ICIs can restore efficacy to the anti-tumor immune response, sometimes resulting in complete and durable tumor regression even in settings of advanced metastatic disease. However, ICIs have not shown clinical benefit in the treatment of immunologically “cold” cancers that are characterized by low levels of T cell infiltrate and low mutation burden resulting in few mutation-created neo-antigens. Further, patients with immunologically hot tumors that initially respond to ICI therapy often show signs of disease progression over time. To improve the extent and duration of response to ICIs in patients with immunologically “hot” tumors and to prime a de novo anti-tumor immune response in patients with “cold” tumors, we propose to combine systemic delivery of ICIs with local delivery of a heterogeneous dose of radiation administered using brachytherapy (BT) at a single tumor with the intent of stimulating an in situ vaccine effect. To date, nearly all approaches to combining radiation and immunotherapy have used external beam radiotherapy (EBRT) which delivers a homogenous dose of radiation. Preclinical studies indicate that the immunogenic effects of radiation are sensitive to dose and field size. Due to its unmatched conformality and dose heterogeneity, BT may confer meaningful advantages over EBRT when it comes to priming an in situ vaccine effect. Our broad hypothesis is that a heterogeneous dose of radiation delivered by BT will allow enhanced activation of multiple dose-dependent immune effects in a single tumor and will elicit a superior in situ vaccine effect in combination with systemically administered immunotherapies compared to homogeneous radiation. In a project that builds upon the ongoing collaborative progress of the Morris and McNeel labs, we will now determine the potency of combining BT with immunotherapy to enhance the immune response against immunologically cold tumors. In murine models, we will: 1) expand on preliminary data showing potent synergy with the combination of BT and ICI, 2) use the inherent dose heterogeneity of BT to characterize dose dependent effects of radiation in a single tumor microenvironment. The insights and treatment regimens developed in these studies should enable rapid translation to clinical testing in patients and potentially for any type of metastatic cancer.

项目摘要/摘要 我们的目标是提高转移性癌症的治愈率。为了实现这一点，我们提出了一种组合模式 刺激和多样化内源性抗肿瘤免疫反应的方法能够识别和 以防止复发和长期无癌症的方式摧毁转移性癌症 生死存亡。我们的意图是制定一项战略，以克服目前限制 免疫疗法。免疫检查点抑制物(ICI；例如抗PD-L1)是一类免疫疗法， 通过阻断肿瘤表面特异性抑制性受体-配体相互作用来调节肿瘤的免疫耐受 T细胞的表面，从而克服T细胞的抑制或衰竭。免疫“热”的患者 肿瘤，其特征是预先存在但已耗尽的抗肿瘤免疫反应，ICIS可以恢复疗效 抗肿瘤免疫反应，有时导致完全和持久的肿瘤消退，即使在 晚期转移性疾病的背景。然而，ICIS在治疗慢性阻塞性肺疾病方面尚未显示出临床疗效。 以低水平T细胞浸润性和低突变负荷为特征的免疫“冷”癌 从而产生很少的突变产生的新抗原。此外，免疫热性肿瘤的患者最初 对ICI治疗的反应通常显示出随着时间的推移疾病进展的迹象。以改善范围和持续时间 免疫“热”肿瘤患者对ICIS的反应，并启动新的抗肿瘤免疫 冷肿瘤患者的反应，我们建议将ICIS全身给药与局部给药相结合 在单个肿瘤上使用近距离放射治疗(BT)进行不同剂量的放射治疗，目的是 刺激一种原位疫苗效应。到目前为止，几乎所有将放射和免疫疗法结合起来的方法都已经 采用外照射(EBRT)，提供均匀剂量的辐射。临床前研究表明 辐射的免疫原性效应对剂量和视野大小很敏感。由于其无与伦比的一致性 和剂量的异质性，在引发AIN时，BT可能比EBRT具有显著的优势 原位疫苗效应。我们的广泛假设是，Bt提供的不同剂量的辐射将允许 增强单个肿瘤中多种剂量依赖的免疫效应的激活，并将在 原位疫苗联合全身免疫疗法与同种免疫疗法的效果比较 辐射。在一个建立在莫里斯和麦克尼尔实验室正在进行的合作进展的项目中，我们 现在将确定Bt与免疫疗法相结合的效力，以增强对 免疫冷冻性肿瘤。在小鼠模型中，我们将：1)扩展初步数据，显示出强大的协同作用 结合Bt和ICI，2)利用Bt固有的剂量异质性来表征剂量 单一肿瘤微环境中辐射的依赖效应。洞察力和治疗方案 在这些研究中开发的应该能够快速转化为患者的临床测试，并有可能 对于任何类型的转移性癌症。