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: 10559653
• 负责人: Justin Charles Jagodinsky
• 金额: $ 1.99万
• 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 2023-05-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10559653
• 关键词: Antigens; Applications Grants; Brachytherapy; Cancer Burden; 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; Indwelling Catheter; 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; Site; Source; Surface; T cell infiltration; 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; checkpoint therapy; cytokine; effector T cell; exhaust; exhaustion; experimental study; immune activation; immune cell infiltrate; 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.

项目总结/摘要 我们的目标是提高转移性癌症的治愈率。为了实现这一目标，我们提出了一种综合方式， 本发明涉及一种刺激内源性抗肿瘤免疫应答并使其多样化的方法， 以防止复发并实现长期无癌的方式破坏转移性癌症 生存我们的意图是制定一项战略，克服目前限制联合国作用的挑战。 免疫疗法免疫检查点抑制剂（ICI;例如抗PD-L1）是一类免疫疗法， 通过阻断肿瘤细胞上的特异性抑制性受体-配体相互作用来调节肿瘤的免疫耐受性。 T细胞表面，从而克服T细胞抑制或耗竭。在免疫学上“热”的患者中， 肿瘤，其特征在于预先存在但耗尽的抗肿瘤免疫应答，ICIs可以恢复疗效 抗肿瘤免疫反应，有时甚至导致完全和持久的肿瘤消退， 晚期转移性疾病。然而，ICIs在治疗以下疾病方面尚未显示出临床益处： 以低水平T细胞浸润和低突变负荷为特征的免疫学“冷”癌 导致很少的突变产生的新抗原。此外，患有免疫热肿瘤的患者最初 对ICI治疗有反应的患者通常随时间显示疾病进展的迹象。为了提高范围和持续时间 免疫学“热”肿瘤患者对ICI的反应， 为了提高“冷”肿瘤患者的免疫应答，我们建议将联合收割机全身性ICI给药与局部注射ICIs联合应用。 使用近距离放射治疗（BT）在单个肿瘤处给予的非均匀剂量放射，目的是 刺激原位疫苗效应。到目前为止，几乎所有结合放射和免疫治疗的方法都有 使用外部射束放射疗法（EBRT），其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射野大小敏感。由于其无与伦比的一致性 和剂量异质性，当涉及到启动一个新的免疫系统时，BT可能比EBRT具有有意义的优势。 原位疫苗效应我们广泛的假设是，BT提供的辐射剂量不均匀， 在单个肿瘤中增强多个剂量依赖性免疫效应的激活，并将引起上级免疫应答。 与均质疫苗相比， 辐射在一个基于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，以增强免疫反应， 免疫冷肿瘤在小鼠模型中，我们将：1）扩展显示有效协同作用的初步数据 结合BT和ICI，2）使用BT固有的剂量异质性来表征剂量 在单一肿瘤微环境中的辐射依赖效应。见解和治疗方案 在这些研究中开发的技术应该能够快速转化为患者的临床试验， 任何类型的转移性癌症。