Tasquinimod as an adjunct to immunotherapies administered peri-operatively

他喹莫德作为围手术期免疫治疗的辅助药物

• 批准号: 10306305
• 负责人: Jana Portnow
• 金额: $ 20.81万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-13 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10306305
• 关键词: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Binding; Biological Products; Brain; Brain Edema; Brain Injuries; Catheters; Cells; Cerebral Edema; Cerebral Edema Management; Chemicals; Clinical Trials; Conduct Clinical Trials; Correlative Study; Cytokine Receptors; Data; Development; Dexamethasone; Dose; Drug Kinetics; Encephalitis; Environment; Excision; Feasibility Studies; Foundations; Future; Glioblastoma; Glioma; Goals; Immune; Immune response; Immune system; Immunologics; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Inflammation; Inflammatory; Inflammatory Response; Lead; Ligands; Liquid substance; Malignant Neoplasms; Maximum Tolerated Dose; Measures; Microdialysis; Mus; Myelogenous; Myeloid-derived suppressor cells; Neoadjuvant Therapy; Oncolytic viruses; Operative Surgical Procedures; PD-1 inhibitors; Pathway interactions; Patient-Focused Outcomes; Patients; Perioperative; Phase; Play; Population; Postoperative Period; Process; Property; Protocols documentation; Reporting; Research Project Grants; Role; S100A9 gene; Safety; Site; Surgically-Created Resection Cavity; Technology; TimeLine; Toxicology; Up-Regulation; Work; anti-PD-1; anti-tumor immune response; autocrine; base; cancer type; chemokine; chimeric antigen receptor T cells; cytokine; data sharing; improved; improved outcome; in vivo; inflammatory marker; mouse model; neoplastic cell; novel; novel strategies; phase 1 study; pre-clinical; preclinical efficacy; receptor for advanced glycation endproducts; response; safety and feasibility; safety study; small molecule inhibitor; standard of care; success; tissue trauma; trafficking; treatment duration; tumor; tumor microenvironment; tumorigenic

PROJECT SUMMARY – PROJECT 2 Although immunotherapy has significantly improved patient survival for many types of cancers, to date no immunotherapeutic agent has shown consistent efficacy against glioblastoma (GBM). Many promising immunotherapy approaches for GBM are administered in the peri-operative period, but, unfortunately, for GBM patients two surgery-related factors work against the success of these immunotherapies: 1) Most GBM patients are treated peri-operatively with high doses of dexamethasone, which suppresses the immune system, and 2) surgical brain injury from tumor resection results in a substantial release of cytokines and chemokines that alter the tumor milieu and support tumor regrowth. Our preclinical data demonstrate the significant role that the receptor for advanced glycation end products (RAGE) pathway plays in the brain’s inflammatory response to surgical brain injury and that the RAGE ligand S100A9 is a key intermediary. The overall goal of this research project is to repurpose tasquinimod, an anti-inflammatory small molecule inhibitor of S100A9, by developing it as an immunotherapy adjunct that will control cerebral edema while diminishing post-surgery activation of the pro-tumor inflammatory response, thus creating a tumor microenvironment that enhances the efficacy of immunotherapies administered in the peri-operative period for the treatment of GBM. We will begin by performing a phase I safety and feasibility study to determine the maximum tolerated dose of tasquinimod when administered in combination with relatively low doses of dexamethasone peri-operatively in GBM patients who undergo tumor resection (Aim 1). We will assess the ability of tasquinimod to reverse myeloid-induced immunosuppression in the tumor microenvironment (Aim 2) by measuring changes in concentrations of cytokines and RAGE ligands in the peritumoral brain interstitium with intracerebral microdialysis and evaluating changes in levels of these inflammatory markers as well as immune cell populations in resection cavity fluid. To determine the immune-modulatory effect of tasquinimod when used in combination with immunotherapy approaches that are administered during the peri-operative period (Aim 3), we will perform preclinical in vivo studies to assess the efficacy of tasquinimod in combination with PD-1 inhibitors, oncolytic viruses, and CAR T cells. By inhibiting the activity of myeloid-derived suppressor cells, tasquinimod could enhance the anti-tumor activity of these emerging immunotherapy technologies, leading to increased efficacy against GBM. Successful completion of these aims would provide a strong foundation to support development of future clinical trials to assess use of tasquinimod alone for controlling cerebral edema and to evaluate tasquinimod in combination with the most promising immunotherapy approach determined in Aim 3 with the goal of improving outcomes for patients with GBM.

项目摘要--项目2 尽管免疫疗法显著提高了许多癌症患者的存活率，但到目前为止还没有 免疫治疗剂对胶质母细胞瘤(GBM)显示出一致的疗效。许多有希望的人 GBM的免疫治疗方法是在围手术期进行的，但不幸的是，对于GBM 患者与手术相关的两个因素阻碍了这些免疫疗法的成功：1)大多数GBM患者 围手术期使用大剂量的地塞米松治疗，这会抑制免疫系统，2) 肿瘤切除所致的外科脑损伤导致大量细胞因子和趋化因子的释放 肿瘤的环境和支持肿瘤的再生。我们的临床前数据表明， 晚期糖基化终产物受体(RAGE)通路在大脑炎症反应中发挥作用 外科脑损伤和RAGE配体S100A9是一个关键的中介。这项研究的总体目标 项目是通过开发S100A9的抗炎小分子抑制剂他斯奎莫特来重新定位它的用途 作为一种免疫治疗的辅助手段，它将控制脑水肿，同时减少术后脑组织的激活 促肿瘤炎症反应，从而创造了一个肿瘤微环境，从而增强了 基底膜的围手术期免疫治疗。我们将从表演开始 一项确定他奎莫特最大耐受量的I期安全性和可行性研究 GBM患者围手术期联合相对小剂量地塞米松治疗 接受肿瘤切除(目标1)。我们将评估他喹莫特逆转髓系诱导的能力。 肿瘤微环境中的免疫抑制(目标2)--通过测量细胞因子浓度的变化 脑内微透析瘤周脑间质中RAGE配体的表达及变化 这些炎性标志物的水平以及切除腔液中的免疫细胞群。要确定 他喹莫特与免疫疗法联合使用时的免疫调节作用 在围手术期给药(目标3)，我们将进行临床前的体内研究以评估 他喹莫特与PD-1抑制剂、溶瘤病毒和CAR T细胞联合应用的疗效。通过抑制 髓系抑制细胞的活性，他喹莫特可增强其抗肿瘤活性。 新兴的免疫治疗技术，提高了对GBM的疗效。成功完成 这些目标将为支持未来临床试验的发展提供坚实的基础，以评估 单用他克莫特控制脑水肿及其联合应用的疗效评价 目标3确定了有希望的免疫治疗方法，目标是改善慢性粒细胞白血病患者的预后 GBM。