A Phase II Clinical Trial in Newly Diagnosed Glioblastoma Patients Treated with WP1066 and Radiation

新诊断的胶质母细胞瘤患者接受 WP1066 和放射治疗的 II 期临床试验

• 批准号: 10658700
• 负责人: Amy Beth Heimberger
• 金额: $ 60.18万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-05 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658700
• 关键词: Animal Model; Animals; Antigen Presentation; Antigen-Presenting Cells; Antitumor Response; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Brain Stem Glioma; CD11c Antigens; CD3 Antigens; Cell physiology; Cells; Cellular immunotherapy; Childhood; Clinical; Clinical Trials; Combined Modality Therapy; Dendritic Cells; Dendritic cell activation; Dependence; Dose; Drug Kinetics; Education; Effectiveness; Excision; Flow Cytometry; Glioblastoma; Gliomagenesis; Goals; Heterogeneity; High Pressure Liquid Chromatography; Human; Immune; Immune response; Immune system; Immunocompromised Host; Immunohistochemistry; Immunologics; Immunosuppression; Immunotherapy; Infiltration; Inflammatory Response; Lesion; MGMT gene; Magnetic Resonance Imaging; Malignant Neoplasms; Maps; Memory; Metastatic malignant neoplasm to brain; Microglia; Modeling; Mus; Myeloid Cells; Natural Immunity; Newly Diagnosed; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Phase II Clinical Trials; Phenotype; Population; Progression-Free Survivals; Radiation; Radiation therapy; Recurrence; Research; Signal Induction; Stat3 protein; T cell infiltration; T-Cell Activation; T-Lymphocyte; Testing; Texture; Tissues; Universities; Validation; adaptive immunity; cancer cell; cohort; first-in-human; immune activation; immune clearance; immunogenicity; improved; nano-string; neuro-oncology; pharmacodynamic biomarker; pharmacologic; phase 3 study; phase I trial; phase II trial; pre-clinical; preclinical study; radiological imaging; response; small molecule inhibitor; standard of care; tumor; tumor microenvironment; tumor-immune system interactions

SUMMARY The brain tumor microenvironment (TME) is dominated by myeloid cell infiltrates which are mostly brain resident microglia and infiltrating glioblastoma-associated myeloid cells (GAMs). Despite this fact, most clinical trials for glioblastoma have been directed to T cell-based immunotherapies, which have failed to impact outcome for most patients. Targeting glioblastoma based on re-education of GAMS to enable immunological clearance is the goal of this clinical trial. The signal transducer and activator of transcription 3 (STAT3) is a negative regulator of both innate and adaptive immunity and this pathway is markedly up regulated in the TME. We have previously developed and tested, in the context of Phase I clinical trials, a first-in-man blood-brain-barrier penetrant small molecule inhibitor of STAT3, designated WP1066. The Phase I trial results have shown that WP1066 is well tolerated and is inhibiting the STAT3 target in immune cells. As a monotherapy, WP1066 treatment has demonstrated the ability to stimulate robust anti-tumor response in multiple preclinical studies that is further enhanced with radiation therapy, which is standard of care for newly diagnosed glioblastoma and is known to increase tumor immunogenicity. Unbiased nanostring analysis of treated tumors revealed that activation of antigen presentation in the TME with the combination treatment. For the research proposed here we want to extend our preclinical findings to newly diagnosed glioblastoma patients. In this clinical trial, we will test the hypothesis that the administration of WP1066 with radiation will induce T cell-dendritic cell cluster interactions in the glioblastoma microenvironment, and this induction, in turn, will increase progression free survival (PFS) for glioblastoma patients. In specific Aim 1, we conduct a Phase II trial with an expansion cohort for the combination of WP1066 and radiation in newly diagnosed MGMT unmethylated glioblastoma patients. In cohort 1, newly diagnosed MGMT unmethylated, IDH1 wild-type glioblastoma patients will be treated with 8 mg/kg of WP1066 while undergoing standard-of-care radiation therapy at a daily dose of 2 Gy. PFS will be used to ascertain if there is indication of treatment benefit. In cohort 2, patients for whom gross total resection was not achieved will be treated with the combination of radiation and WP1066 with the intent of obtaining treated tumor, if a surgically amenable lesion is present. Such tissue would allow for analysis of TME immune activation and cluster interactions, drug concentrations and target engagement in Aim 2. Aim 2 will also use longitudinal textural MRI analysis to correlate inflammatory responses in the TME by using our STAT3-specific multiplex immune fluorescent panel and complementary ex vivo flow cytometry and nanostring profiling. STAT3 target inhibition, including within specific immune cell populations, will be ascertained through use of the multiplex panel, which will also inform regarding the induction of cluster interactions in the tumor. HPLC quantification of WP1066 concentrations in both enhancing and non-enhancing tumor will be used to determine drug pharmacokinetics. In Aim 3, we will clarify which human GAMs in the TME trigger T cell activation, and if such activation is altered by STAT3 inhibition.

摘要 脑肿瘤微环境(TME)以髓系细胞为主，主要分布于脑内。 小胶质细胞和浸润性胶质母细胞瘤相关髓系细胞(GAM)。尽管如此，大多数临床试验 胶质母细胞瘤已被用于基于T细胞的免疫治疗，但这对大多数人的预后都没有影响 病人。目标是基于GAMS的再教育来靶向胶质母细胞瘤，以实现免疫清除 这项临床试验的。信号转导和转录激活子3(STAT3)是两者的负调控因子 先天免疫和获得性免疫，这一途径在TME中显著上调。我们之前已经 在第一阶段临床试验中开发和测试了一种首例人血脑屏障穿透剂 STAT3的分子抑制剂，命名为WP1066。一期试验结果表明，WP1066性能良好 耐受并抑制免疫细胞中的STAT3靶标。作为单一疗法，WP1066治疗已经 在多项临床前研究中证明了激发强大的抗肿瘤反应的能力，这是进一步的 增强放射治疗，这是新诊断的胶质母细胞瘤的标准护理，并已知 增强肿瘤免疫原性。对治疗的肿瘤进行的无偏纳米串分析表明， 联合治疗时TME中的抗原递呈。对于这里提出的研究，我们想要 将我们的临床前发现扩展到新诊断的胶质母细胞瘤患者。在这次临床试验中，我们将测试 WP1066联合辐射可诱导T细胞-树突状细胞群相互作用的假说 胶质母细胞瘤的微环境，这种诱导，反过来将增加患者的无进展生存率(PFS 胶质母细胞瘤患者。在具体目标1中，我们进行了组合的扩展队列的第二阶段试验 WP1066和辐射在新诊断的MGMT非甲基化胶质母细胞瘤患者中的作用。在队列1中，新 诊断为MGMT未甲基化、IDH1野生型胶质母细胞瘤的患者将接受8 mg/kg的WP1066治疗 同时接受标准护理放射治疗，每日剂量为2GY。将使用PFS来确定是否有 是治疗益处的指标。在队列2中，未达到大体全切除的患者将是 用放射和WP1066的组合治疗，目的是获得治疗的肿瘤，如果手术治疗 存在可屈从的损伤。这样组织将允许分析TME免疫激活和聚集 AIM 2中的相互作用、药物浓度和靶点接触。AIM 2还将使用纵向纹理磁共振 用我们的STAT3特异性多重免疫分析TME中的相关炎症反应 荧光板和互补的体外流式细胞术和纳米线分析。STAT3靶标抑制， 包括在特定的免疫细胞群体中，将通过使用多重小组来确定，该小组 还将告知有关在肿瘤中诱导簇相互作用的信息。高效液相色谱法测定WP1066的含量 增强型和非增强型肿瘤中的浓度将用于确定药物的药代动力学。在……里面 目的3，我们将阐明TME中哪些人类GAMs触发T细胞激活，以及这种激活是否被改变 STAT3抑制作用。