Enhancing Systemic Delivery of Oncolytic Viruses for Cancer Therapy

增强溶瘤病毒的全身递送用于癌症治疗

• 批准号: 8387981
• 负责人: Richard G. Vile
• 金额: $ 25.73万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8387981
• 关键词: Animals; Blood Circulation; Blood Vessels; Clinic; Clinical; Clinical Trials; Complement; Cyclophosphamide; Data; Depressed mood; Development; Disease; Dose; Engineering; Genes; Goals; Grant; Human; Immune; Immune system; Integration Host Factors; Intravenous; Lead; Malignant Neoplasms; Metastatic to; Modification; Mus; Nature; Neoplasm Metastasis; Oncolytic; Oncolytic viruses; Patients; Phase I Clinical Trials; Pre-Clinical Model; Protocols documentation; Regimen; Reovirus; Safety; Serotyping; Testing; Therapeutic; Time; Tissues; Toxic effect; Transgenes; Tumor Immunity; Vascular Permeabilities; Vesicular stomatitis Indiana virus; Viral; Virus; authority; cancer cell; cancer therapy; cellular transduction; design; experience; improved; neoplastic cell; neutralizing antibody; novel; prevent; research study; response; subcutaneous; tumor; vector

ABSTRACT A major goal of oncolytic virotherapy is systemic delivery to metastatic disease. However, currently, i.v. virus cannot access tumors at sufficient levels to achieve regression(s). Therefore, novel protocols must be developed by which viruses can survive in the circulation long enough to access tumors in the face of anti viral neutralizing antibodies (NAb), components of the circulation which inactivate the viruses, and vascular barriers preventing extra-vasation. In our Phase I clinical trial of systemic delivery of Reovirus, there is encouraging evidence of virus reaching metastatic tumors. We will now return to our pre-clinical models, using Vesicular Stomatitis Virus (VSV), to treat B16 murine tumors in immune competent mice. To enhance virus survival in the circulation we will use cyclophosphamide (CPA), which suppresses anti-viral innate/adaptive responses and should be acceptable to regulatory authorities as an adjunct to systemic virotherapy. We have shown that, depending upon dose/timing of CPA, high levels of systemic virus can access s.c. tumors and both toxicity, and levels of NAb (which control access of the virus to systemic tissues), can be regulated. We will also target the major physical barrier of the tumor vasculature and have shown that induction of vascular permeability safely facilitates access of circulating virus into tumors along with significant therapy. Therefore, our overall hypothesis is that it will be possible to develop clinically applicable protocols by which oncolytic viruses can be delivered systemically to established tumors, at therapeutic levels, in a fully immune competent host. To test this hypothesis, we will optimize the tumor localization/replication of intravenous oncolytic virus following a first administration in an immune-competent host (Aim 1). In Specific Aims 2 and 3, we will optimize the tumor localization/replication of i.v. virus using repeat administrations by modifying the timing of administration, the nature of the virus (Aim 2) or the host immune system (Aim 3). Finally, we will combine the optimal conditions for systemic delivery from Aims 1-3 to treat well-established subcutaneous and metastatic disease (Aim 4). These experiments will drive the initiation of new trials of VSV as a systemic agent at the Mayo Clinic to complement our ongoing trials with other oncolytic viruses.

抽象的 溶瘤病毒疗法的一个主要目标是全身递送至转移性疾病。然而，目前， 静脉注射病毒无法以足够的水平进入肿瘤以实现消退。因此，新颖的协议 必须开发出使病毒能够在循环中存活足够长的时间以进入肿瘤的方法 抗病毒中和抗体（NAb）的表面，它是循环系统的成分，可灭活病毒 病毒和防止外渗的血管屏障。在我们的系统性 I 期临床试验中 递送呼肠弧病毒，有令人鼓舞的证据表明病毒到达转移性肿瘤。我们现在将 返回我们的临床前模型，使用水泡性口炎病毒 (VSV) 治疗 B16 小鼠肿瘤 具有免疫能力的小鼠。为了提高病毒在循环中的存活率，我们将使用环磷酰胺 （CPA），它抑制抗病毒先天/适应性反应，应该为监管机构所接受 当局将其作为全身病毒疗法的辅助手段。我们已经证明，取决于剂量/时间 CPA 中，高水平的系统性病毒可以进入皮下组织。肿瘤和毒性以及 NAB 水平 （控制病毒进入全身组织），可以被调节。我们还将针对主要 肿瘤脉管系统的物理屏障，并表明诱导血管通透性 安全地促进循环病毒进入肿瘤以及有效的治疗。因此，我们的 总体假设是，有可能开发出临床适用的方案，通过该方案 溶瘤病毒可以在治疗水平上以完全的方式全身递送至已建立的肿瘤。 具有免疫能力的宿主。为了检验这个假设，我们将优化肿瘤定位/复制 在免疫功能正常的宿主中首次施用后静脉注射溶瘤病毒（目标 1）。在 具体目标 2 和 3，我们将优化静脉注射的肿瘤定位/复制。病毒使用重复 通过修改给药时间、病毒性质（目标 2）或宿主来进行给药 免疫系统（目标 3）。最后，我们将结合系统递送的最佳条件 目标 1-3 治疗已确定的皮下和转移性疾病（目标 4）。这些实验 将推动梅奥诊所启动 VSV 作为全身性药物的新试验，以补充我们的研究 正在进行其他溶瘤病毒的试验。