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: 7993072
• 负责人: Richard G. Vile
• 金额: $ 27.37万
• 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 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7993072
• 关键词: Animals; Blood Circulation; Blood Vessels; Clinic; Clinical; Clinical Trials; Complement; Cyclophosphamide; Data; Depressed mood; Development; Disease; Dose; Engineering; Genes; Goals; Grant; Health; 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The experiments in this grant aim to increase the efficiency with which viruses, specifically engineered to destroy cancer cells, can be delivered through the bloodstream of patients with metastatic (widespread) cancer. If successful, they will lead to implementation of clinical trials to test both the safety and efficacy of this approach as a novel form of cancer treatment.

描述（由申请人提供）：溶瘤病毒疗法的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，必须开发新的方案，使病毒能够在循环中存活足够长的时间，以便在面对抗病毒中和抗体（NAb）、灭活病毒的循环成分以及防止外渗的血管屏障时进入肿瘤。在我们全身递送呼肠孤病毒的一期临床试验中，有令人鼓舞的证据表明病毒到达转移性肿瘤。现在，我们将回到我们的临床前模型，使用水泡性口炎病毒 (VSV) 治疗免疫能力强的小鼠中的 B16 小鼠肿瘤。为了提高病毒在循环中的存活率，我们将使用环磷酰胺（CPA），它可以抑制抗病毒先天/适应性反应，并且应该被监管机构接受作为全身病毒治疗的辅助手段。我们已经证明，根据 CPA 的剂量/时间，高水平的全身性病毒可以进入皮下。肿瘤以及毒性和 NAb 水平（控制病毒进入全身组织）都可以得到调节。我们还将针对肿瘤脉管系统的主要物理屏障，并已证明诱导血管通透性可以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，将有可能开发出临床适用的方案，通过该方案，可以在完全免疫能力的宿主中，以治疗水平将溶瘤病毒全身递送至已建立的肿瘤。为了检验这一假设，我们将在免疫功能正常的宿主中首次给药后优化静脉溶瘤病毒的肿瘤定位/复制（目标 1）。在具体目标 2 和 3 中，我们将优化静脉注射的肿瘤定位/复制。通过修改给药时间、病毒性质（目标 2）或宿主免疫系统（目标 3），重复给药来消灭病毒。最后，我们将结合目标 1-3 中全身给药的最佳条件来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，以补充我们正在进行的其他溶瘤病毒试验。公共健康相关性：本次资助的实验旨在提高专门设计用于破坏癌细胞的病毒通过转移性（广泛性）癌症患者的血流传递的效率。如果成功，他们将实施临床试验，以测试这种方法作为一种新型癌症治疗方法的安全性和有效性。