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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

基本信息

批准号：
10696191
负责人：
Jana Portnow
金额：
$ 5.68万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
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/10696191
关键词：
Ablation Adrenal Cortex Hormones Anti-Inflammatory Agents Binding Biological Products Brain Brain Edema Brain Injuries Brain Neoplasms Catheters Cells Cerebral Edema Cerebral Edema Management Chemicals Clinical Trials Conduct Clinical Trials Correlative Study Data Development Dexamethasone Dose Drug Kinetics Encephalitis Environment Excision Feasibility Studies Foundations Future Glioblastoma Glioma Goals Growth Immune Immune response Immune system Immunologics Immunosuppression Immunotherapeutic agent Immunotherapy Inflammation Inflammatory Inflammatory Response Institution 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 Toxicology Up-Regulation Work anti-PD-1 anti-tumor immune response autocrine brain surgery cancer type chemokine chimeric antigen receptor T cells cytokine data sharing efficacy evaluation immunoregulation improved improved outcome in vivo inflammatory marker manufacture mouse model neoplastic cell novel novel strategies phase 1 study pre-clinical preclinical efficacy receptor receptor for advanced glycation endproducts response safety and feasibility small molecule inhibitor standard of care success timeline tissue trauma trafficking treatment duration tumor tumor microenvironment tumorigenic

项目摘要

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.

项目概要----项目2 尽管免疫疗法显著改善了许多类型癌症的患者生存率，但迄今为止，免疫抑制剂已经显示出针对胶质母细胞瘤（GBM）的一致功效。许多有前途 GBM的免疫治疗方法在围手术期施用，但不幸的是，对于GBM，两个与手术相关的因素不利于这些免疫疗法的成功：1）大多数GBM患者在围手术期用高剂量地塞米松治疗，其抑制免疫系统，以及2）来自肿瘤切除术的手术脑损伤导致细胞因子和趋化因子的大量释放，支持肿瘤再生。我们的临床前数据表明，晚期糖基化终末产物受体（receptor for advanced glycation end products，RECEPTOR）通路在大脑对糖基化终末产物的炎症反应中起作用。手术性脑损伤，而ESTA配体S100 A9是一个关键的中介。本研究的总体目标是一个项目是重新利用他喹莫德，一种抗炎的S100 A9小分子抑制剂，作为一种免疫治疗辅助手段，将控制脑水肿，同时减少手术后激活的促肿瘤炎性反应，从而产生肿瘤微环境，在围手术期施用免疫疗法以治疗GBM。我们将开始表演 I期安全性和可行性研究，以确定他喹莫德的最大耐受剂量，在GBM患者中，在围手术期联合使用相对低剂量的地塞米松，接受肿瘤切除术（目标1）。我们将评估他喹莫德逆转骨髓诱导的白血病的能力。通过测量细胞因子浓度的变化，在肿瘤微环境中进行免疫抑制（目的2）脑内微透析法检测肿瘤周围脑组织中配体的变化这些炎症标志物的水平以及切除腔液中的免疫细胞群。以确定当与免疫疗法联合使用时，他喹莫德的免疫调节作用接近于在围手术期（目标3）给药，我们将进行临床前体内研究，以评估他喹莫德与PD-1抑制剂、溶瘤病毒和CAR T细胞组合的功效。通过抑制骨髓来源的抑制细胞的活性，他喹莫德可以增强这些抑制细胞的抗肿瘤活性。新兴的免疫治疗技术，提高了针对GBM的功效。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，单独的他喹莫德用于控制脑水肿，并评价他喹莫德与大多数目标3中确定的有前景的免疫治疗方法，其目标是改善患有以下疾病的患者的结局： GBM。