Oncolytic virus-mediated target delivery of a therapeutic antibody fragment in glioblastoma

溶瘤病毒介导的胶质母细胞瘤治疗抗体片段的靶向递送

基本信息

批准号：
9908664
负责人：
Anne-Marie Carbonell
金额：
$ 30万
依托单位：
ONCOSYNERGY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-20 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908664
关键词：
Address Biodistribution Blocking Antibodies Blood - brain barrier anatomy Brain Brain Neoplasms Bypass Cell Survival Characteristics Chemosensitization Clinical Trials Collaborations Convection Development Diagnosis Disease Dose-Limiting Drug Delivery Systems Drug Targeting Engineering Ensure FDA approved Generations Glioblastoma Growth Growth Factor HSV vector Herpesvirus 1 Human Immune Immunoglobulin Fragments In Vitro In complete remission Infiltrative Growth Inflammatory Injections Integrins Interferons Location Malignant Neoplasms Malignant neoplasm of ovary Mediating Modeling Monoclonal Antibodies Oncogenic Oncolytic viruses Operative Surgical Procedures Orphan Drugs Outcome Patients Pattern Phase Primary Brain Neoplasms Recurrence Resistance Route Signal Transduction Simplexvirus Small Business Technology Transfer Research Solid System Testing Texas Therapeutic Therapeutic antibodies Time Toxic effect Treatment Efficacy Treatment outcome Universities Viral Work Xenograft Model Xenograft procedure adaptive immune response base bevacizumab chemoradiation cytokine cytotoxicity effective therapy empowered improved in vivo macrophage malignant breast neoplasm melanoma migration multimodality neoplastic cell novel novel strategies novel therapeutics oncolytic virotherapy pre-clinical systemic toxicity targeted delivery therapeutic candidate therapeutic development therapy resistant tumor tumor growth vector

项目摘要

PROJECT SUMMARY More than 10,000 patients are diagnosed each year with glioblastoma, the most common primary brain tumor. Current treatments are inadequate and there have been no major therapeutic breakthroughs in decades. Hence, there is an urgent need to develop novel strategies to address this devastating disease. However, development of an effective treatment for glioblastoma is severely hampered by 1) the blood-brain barrier (BBB), 2) an infiltrative growth pattern, 3) rapid development of therapeutic resistance, and, in many cases, 4) dose-limiting toxicity due to systemic exposure. To overcome these challenges, OncoSynergy, Inc. in collaboration with Dr. Balveen Kaur (University of Texas-Houston) is developing a novel therapeutic delivery approach to address each of these hurdles. This approach consists of a herpes simplex virus type 1-based oncolytic virus (HSV) that expresses an anti-CD29 (aCD29) antibody fragment and intracranial administration to the tumor and/or tumor infiltrated brain (TIB) via convection-enhanced delivery (CED). Many HSV vectors have been generated and are currently being tested at different stages in clinical trials for glioblastoma. However, complete responses or therapeutic efficacy have rarely been observed, indicating significant improvements in HSV therapy are necessary. Remarkably, our recent study showed that CD29 blockade using OS2966, a humanized anti-CD29 monoclonal antibody, enhances the efficacy of HSV in an orthotopic xenograft model of glioblastoma. Specifically, OS2966 treatment decreases interferon signaling and pro- inflammatory cytokine induction in HSV-treated tumor cells and inhibits migration of macrophages, resulting in enhanced HSV replication and cytotoxicity. Intratumoral OS2966 treatment also significantly enhances HSV replication and HSV-mediated anti-tumor efficacy in orthotopic xenograft model of glioblastoma. Importantly, OS2966 is FDA Orphan Drug designated in the treatment of glioblastoma and, in March, 2019, OncoSynergy has received IND clearance of OS2966 by the FDA as a monotherapy in recurrent glioblastoma (IND 139483). Hence, logically extend our studies, we propose to develop a novel HSV-mediated delivery system (i.e., HSV encoding a fragment of OS2966, which will be secreted outside viral infected tumor cells) to precisely enhance the synergistic effects of HSV and CD29 blockade. We will engineer an HSV encoding a fragment of OS2966 (HSV-aCD29) and determine in vitro and in vivo efficacy of HSV-aCD29. The successful completion of this Phase I STTR project will result in the generation of a multimodal therapeutic approach empowered by a novel HSV-mediated drug delivery system for the treatment of glioblastoma. Building on this milestone, our Phase II STTR project will further optimize this novel treatment regime in preclinical glioblastoma models and pursue IND-enabling studies to support IND submission.

项目摘要每年有10,000多名患者患有胶质母细胞瘤，这是最常见的原发性脑肿瘤。目前的治疗不足，几十年来没有重大的治疗突破。因此，迫切需要制定新的策略来解决这种毁灭性疾病。然而， 1）血脑屏障的有效治疗可严重阻碍（BBB），2）一种渗透性的生长模式，3）治疗耐药性的快速发展，在许多情况下，4）由于全身暴露而导致的剂量限制毒性。为了克服这些挑战，Oncosynergy，Inc。与Balveen Kaur博士（德克萨斯 - 霍斯顿大学）的合作正在开发一种新颖的治疗性交付解决这些障碍的方法。这种方法由单纯疱疹病毒基于1型的疱疹组成表达抗CD29（ACD29）抗体片段和颅内给药的溶瘤病毒（HSV）通过对流增强递送（CED）到肿瘤和/或肿瘤浸润的大脑（TIB）。许多HSV向量已经生成，目前正在不同阶段进行胶质母细胞瘤试验中的测试。但是，很少观察到完整的反应或治疗功效，表明显着需要改善HSV疗法。值得注意的是，我们最近的研究表明，CD29封锁使用 OS2966是一种人源化抗CD29单克隆抗体，增强了HSV在原位中的疗效胶质母细胞瘤的异种移植模型。具体而言，OS2966治疗降低了干扰素信号传导和促进 HSV处理的肿瘤细胞中的炎症细胞因子诱导并抑制巨噬细胞的迁移，导致增强的HSV复制和细胞毒性。肿瘤内OS2966治疗也显着增强了HSV 胶质母细胞瘤的原位异种移植模型中的复制和HSV介导的抗肿瘤功效。重要的是， OS2966是胶质母细胞瘤治疗中指定的FDA孤儿药，2019年3月，OncoSynergy FDA作为复发性胶质母细胞瘤的单一疗法（IND 139483）获得了OS2966的IND清除。因此，从逻辑上扩展了我们的研究，我们建议开发一种新型的HSV介导的输送系统（即HSV 编码OS2966的片段，该片段将在病毒感染的肿瘤细胞之外分泌）以精确增强 HSV和CD29封锁的协同作用。我们将设计一个编码OS2966片段的HSV （HSV-ACD29）并确定HSV-ACD29的体外和体内功效。成功完成 I期STTR项目将导致产生一种由新颖的多模式治疗方法 HSV介导的药物输送系统用于治疗胶质母细胞瘤。以这个里程碑为基础，我们的第二阶段 STTR项目将进一步优化临床前胶质母细胞瘤模型中的这种新型治疗方案并追求辅助研究以支持IND提交。