STINGing GBM: A First-in- Man Clinical Trial in Surgical Resectable Recurrent GBM

刺痛 GBM：可手术切除复发性 GBM 的首次人体临床试验

• 批准号: 10626394
• 负责人: Amy Beth Heimberger
• 金额: $ 28.58万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-17 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10626394
• 关键词: Address; Aftercare; Agonist; Biopsy; CD14 gene; CXCL10 gene; Canis familiaris; Catheters; Cells; Cellular Stress; Cellular Structures; Characteristics; Clinical; Clinical Data; Clinical Research; Clinical Trials; Conduct Clinical Trials; Core Biopsy; Cytometry; Cytoplasm; Cytotoxic T-Lymphocytes; DNA; Data; Diameter; Dinucleoside Phosphates; Dose; Environment; Evaluable Disease; Flow Cytometry; Gene Activation; Gene Targeting; Genes; Glioblastoma; Glioma; Goals; Growth; Human; Hypermethylation; IRF3 gene; Image; Immune; Immune checkpoint inhibitor; Immune response; Immunofluorescence Immunologic; Immunologics; Implant; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Injections; Interferons; Kinetics; MGMT gene; Macrophage; Malignant neoplasm of brain; Maximum Tolerated Dose; Mediating; Metabolism; Methylation; Microdialysis; Modeling; Molecular; Myelogenous; Myeloid Cells; NF-kappa B; Natural Immunity; Newly Diagnosed; Nucleosides; Operative Surgical Procedures; Outcome; Pathway interactions; Patient imaging; Patients; Periodicity; Peripheral Blood Mononuclear Cell; Phase; Phase I Clinical Trials; Phenotype; Positron-Emission Tomography; Production; Radiation; Radiation therapy; Recurrence; Recurrent tumor; Resectable; Resected; Resistance; Sampling; Signal Transduction; Stimulator of Interferon Genes; T cell infiltration; T-Lymphocyte; Testing; Therapeutic; Thymidine; Thymidine Phosphorylase; Time; Tracer; Treatment Efficacy; Tumor Tissue; Tumor-associated macrophages; biomarker selection; chemokine; cohort; contrast enhanced; cytokine; design; digital; effector T cell; efficacy evaluation; first-in-human; humanized mouse; immune checkpoint; immune clearance; interest; monocyte; nano-string; neoplastic cell; patient subsets; pre-clinical; pre-clinical research; preclinical study; predictive marker; programs; promoter; radiological imaging; response; sensor; standard of care; synergism; temozolomide; tissue culture; trafficking; transcriptome sequencing; translational approach; tumor; tumor microenvironment; uptake

PROJECT 2: SUMMARY The glioblastoma (GBM) microenvironment is dominated by myeloid cell infiltrates. Results from multiple studies indicate these tumor-associated myeloid cells (TAMS) as supporting GBM growth. The goal of this project is to reprogram TAMS for immunologic anti-tumor activity. Stimulator of interferon genes (STING) is a widely expressed sensor of cellular stress that is activated by the presence of DNA in the cytoplasm. Distinct from most other immune agonists, STING activation re-educates tumor supportive M2 macrophage TAMS toward a proinflammatory anti- tumor M1 phenotype. Macrophage proinflammatory phenotypic conversion, in turn, promotes cytotoxic T cell infiltration of and activity against tumor. We have developed a high potency STING agonist, IACS-8803, with marked antitumor activity when tested in humanized mice bearing human GBM, and in canines with spontaneously arising high-grade gliomas. In addressing the clinical potential of this agonist in treating GBM, we will first determine its effect on interferon responses, using [18F]FLT PET, when IACS-8803 is administered to patients with recurrent tumor. This first-in-man Phase I clinical trial will inform regarding the range in IACS-8803 activity that is observed across the cohort of treated patients, with activity results compared against tumor molecular characteristics, and patient clinical data. The clinical trial will include analysis of several unique endpoints, among which are target engagement and longitudinal kinetics of IACS-8803 induced T cell chemokine expression such as CXCL10. In addition, a window-of-opportunity patient cohort will receive direct intratumoral administration of IACS-8803, and whose results will be compared against those from patients that have received systemic administration of standard-of-care therapeutics. The PET Imaging results will be analyzed with respect to inflammatory immune response in resected tumors from active vs. non-active tracer regions in post-STING treated subjects, using multiplex immunofluorescence, CyTOF, and/or mass cytometry. This clinical study will ultimately provide sufficient data to make a clear go/no go determination for later-stage clinical trials based on sufficient target engagement in the tumor microenvironment. While conducting this clinical trial, we will move forward with preclinical research by evaluating the efficacy of combined IAC-8803 + radiation in orthotopic models of GBM. Results from these preclinical studies will inform whether STING agonist and radiation treatment should be tested in patients with newly diagnosed GBM, and whose tumors have unmethylated MGMT promoter, and as such, do not require treatment with temozolomide.

项目 2：总结 胶质母细胞瘤（GBM）微环境以骨髓细胞浸润为主。多项研究的结果 表明这些肿瘤相关骨髓细胞 (TAMS) 支持 GBM 生长。该项目的目标是 重新编程 TAMS 以获得免疫抗肿瘤活性。干扰素基因刺激子（STING）是一种广泛表达的 细胞应激传感器，由细胞质中 DNA 的存在而激活。与大多数其他免疫不同 激动剂，STING 激活重新教育肿瘤支持性 M2 巨噬细胞 TAMS 朝向促炎抗- 肿瘤M1表型。巨噬细胞促炎表型转化反过来促进细胞毒性 T 细胞 肿瘤的浸润和活性。我们开发了一种高效 STING 激动剂 IACS-8803， 在携带人类 GBM 的人源化小鼠和携带人类 GBM 的犬科动物中进行测试时，具有显着的抗肿瘤活性 自发产生的高级神经胶质瘤。为了探讨这种激动剂治疗 GBM 的临床潜力，我们 当 IACS-8803 给药时，将首先使用 [18F]FLT PET 确定其对干扰素反应的影响 肿瘤复发的患者。这项首次人体 I 期临床试验将告知 IACS-8803 中的范围 在接受治疗的患者队列中观察到的活性，并将活性结果与肿瘤进行比较 分子特征和患者临床数据。临床试验将包括对几种独特的分析 终点，其中包括 IACS-8803 诱导的 T 细胞趋化因子的靶标参与和纵向动力学 表达如 CXCL10。此外，机会窗口患者队列将接受直接瘤内注射 施用 IACS-8803，其结果将与接受过 IACS-8803 治疗的患者的结果进行比较 标准护理治疗的系统管理。 PET 成像结果将根据以下方面进行分析 STING 后活性与非活性示踪剂区域切除肿瘤的炎症免疫反应 使用多重免疫荧光、CyTOF 和/或质谱流式细胞仪对治疗的受试者进行治疗。这项临床研究将 最终提供足够的数据，为后期临床试验做出明确的进行/不进行的决定 肿瘤微环境中充分的靶标参与。在进行这项临床试验时，我们将采取行动 通过评估 IAC-8803 + 放射组合在原位治疗中的功效来推进临床前研究 GBM 模型。这些临床前研究的结果将告知 STING 激动剂和放射治疗是否有效 应在新诊断的 GBM 且其肿瘤具有未甲基化 MGMT 启动子的患者中进行测试， 因此，不需要用替莫唑胺治疗。