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

• 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
• 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

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 每年有超过10，000名患者被诊断患有胶质母细胞瘤，这是最常见的原发性脑肿瘤。 目前的治疗是不够的，几十年来没有重大的治疗突破。 因此，迫切需要制定新的战略来应对这一毁灭性疾病。然而，在这方面， 胶质母细胞瘤的有效治疗方法的开发受到以下因素的严重阻碍：1）血脑屏障 (BBB)2）浸润性生长模式，3）治疗抗性的快速发展，以及，在许多情况下，4） 由于全身暴露而导致的剂量限制性毒性。为了克服这些挑战，OncoSynergy，Inc.在 与Balveen Kaur博士（德克萨斯大学休斯顿分校）合作，正在开发一种新的治疗药物， 解决这些障碍的方法。这种方法包括一个单纯疱疹病毒1型为基础的 表达抗CD29（aCD29）抗体片段的溶瘤病毒（HSV）和颅内给药 通过对流增强递送（CED）递送至肿瘤和/或肿瘤浸润脑（TIB）。许多HSV载体 目前正在胶质母细胞瘤临床试验的不同阶段进行测试。 然而，很少观察到完全反应或治疗功效，表明显著的 HSV治疗的改进是必要的。值得注意的是，我们最近的研究表明，CD29阻断使用 人源化抗CD29单克隆抗体OS 2966增强HSV在原位免疫组化中的功效。 胶质母细胞瘤异种移植模型。具体而言，OS 2966治疗降低了干扰素信号传导和促甲状腺激素分泌。 HSV处理的肿瘤细胞中的炎性细胞因子诱导，并抑制巨噬细胞的迁移，导致 增强HSV复制和细胞毒性。瘤内OS 2966治疗也显著增强HSV 在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， OS 2966是FDA指定用于治疗胶质母细胞瘤的孤儿药，2019年3月，OncoSynergy 已获得FDA批准的OS 2966作为复发性胶质母细胞瘤单药治疗的IND批准（IND 139483）。 因此，从逻辑上扩展我们的研究，我们提出开发一种新的HSV介导的递送系统（即，HSV 编码OS 2966的片段，其将分泌到病毒感染的肿瘤细胞外）以精确地增强 HSV和CD29阻断的协同作用。我们将设计一个编码OS2966片段的HSV HSV-a ⑶ 29的体外和体内功效。成功完成本 I期STTR项目将产生一种新型的多模式治疗方法， HSV介导的药物递送系统用于胶质母细胞瘤的治疗。在这一里程碑的基础上，我们的第二阶段 STTR项目将在临床前胶质母细胞瘤模型中进一步优化这种新的治疗方案， 支持IND提交的IND使能研究。