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

项目2：概要 胶质母细胞瘤（GBM）微环境由髓样细胞浸润支配。多项研究的结果 表明这些肿瘤相关髓样细胞（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。干扰素基因刺激因子（STING）是一种广泛表达的 细胞应激的传感器，被细胞质中DNA的存在激活。与大多数其他免疫 激动剂，STING活化将肿瘤支持性M2巨噬细胞TAMS重新教育为促炎性抗炎药。 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 对肿瘤浸润和抗肿瘤活性。我们已经开发了一种高效STING激动剂IACS-8803， 当在携带人GBM的人源化小鼠和携带人GBM的犬中测试时， 自发性高级别胶质瘤在探讨这种激动剂治疗GBM的临床潜力时，我们 将首先使用[18F]FLT PET确定IACS-8803给药时对干扰素应答的影响， 肿瘤复发患者。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 分子特征和患者临床数据。临床试验将包括分析几个独特的 终点，其中包括IACS-8803诱导的T细胞趋化因子的靶向接合和纵向动力学 例如CXCL 10。此外，一个机会窗口患者队列将接受直接瘤内注射。 施用IACS-8803的患者的结果，并且将其结果与已经接受IACS-8803的患者的结果进行比较。 标准治疗剂的全身给药。将分析PET成像结果， STING后活性与非活性示踪剂区域切除肿瘤中的炎症免疫应答 治疗的受试者，使用多重免疫荧光、CyTOF和/或质谱细胞术。本临床研究将 最终提供足够的数据，以便根据以下因素为后期临床试验做出明确的通过/不通过决定 在肿瘤微环境中充分的靶向接合。在进行这项临床试验的同时，我们将 通过评估IAC-8803 +联合放疗在原位肿瘤中的疗效， 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 应在新诊断的GBM患者中进行测试，并且其肿瘤具有未甲基化的MGMT启动子， 因此不需要用替莫唑胺治疗。

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.