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.

概括 脑肿瘤微环境（TME）主要由髓样细胞浸润，主要是脑常存 小胶质细胞和浸润胶质母细胞瘤相关的髓样细胞（GAM）。尽管这一事实，大多数临床试验 胶质母细胞瘤已针对基于T细胞的免疫疗法，这些免疫疗法未影响大多数的预后 患者。靶向基于重新教育的胶质母细胞瘤以实现免疫学清除是目标 这项临床试验。转录3（STAT3）的信号换能器和激活因子是两者的负调节剂 先天性和适应性免疫，该途径在TME中明显调节。我们以前有 在第一阶段临床试验的背景下，开发和测试了第一组的血脑屏障渗透剂小 STAT3的分子抑制剂，指定为WP1066。第一阶段试验结果表明WP1066很好 耐受性并抑制免疫细胞中的STAT3靶标。作为单一疗法，WP1066治疗具有 证明了在多个临床前研究中刺激强大的抗肿瘤反应的能力，这是进一步的 通过放射疗法增强，这是新诊断的胶质母细胞瘤的护理标准，已知 增加肿瘤免疫原性。对治疗肿瘤的无偏纳米静脉分析表明，激活的激活 联合处理中的TME中的抗原表现。对于这里提出的研究，我们想 将我们的临床前发现扩展到新诊断的胶质母细胞瘤患者。在这项临床试验中，我们将测试 假设WP1066用辐射的给药将诱导T细胞树突状细胞簇相互作用 胶质母细胞瘤微环境以及这种诱导又将增加无进展生存（PFS） 胶质母细胞瘤患者。在特定目标1中，我们进行了II期试验，并进行了膨胀队列的组合 WP1066和新诊断的MGMT未甲基化胶质母细胞瘤患者的辐射。在1中，新的 诊断为未甲基化的MGMT IDH1野生型胶质母细胞瘤患者将用8 mg/kg的WP1066治疗 同时以2 Gy的每日剂量进行护理标准放射治疗。 PFS将用于确定是否存在 是治疗益处的指示。在队列2中，未实现总切除的患者将是 用辐射和WP1066的组合处理，目的是获得治疗的肿瘤 存在正态病变。这种组织将允许分析TME免疫激活和簇 AIM 2中的相互作用，药物浓度和目标参与。AIM 2还将使用纵向纹理MRI 分析通过使用我们的STAT3特异性多重免疫来将TME中的炎症反应相关联 荧光面板和互补的离体流式细胞仪和纳米弦分析。 STAT3目标抑制， 包括在特定的免疫细胞群体中，将通过使用多路复用面板来确定 还将告知肿瘤中簇相互作用的诱导。 WP1066的HPLC定量 增强和非增强肿瘤的浓度将用于确定药代动力学。在 AIM 3，我们将阐明TME中的哪些人类游戏触发T细胞激活，并且是否通过这种激活改变了 STAT3抑制。