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传递转移性疾病。但是，目前，i.v.病毒无法在足够水平的情况下进入肿瘤以实现回归。因此，必须开发新的方案，该方案可以通过抗病毒中和抗体（NAB），循环的成分，使病毒失活的循环系统和血管障碍，并防止外部病。在我们的I阶段依次递送依孢病毒的临床试验中，有令人鼓舞的证据表明病毒达到转移性肿瘤。现在，我们将使用囊泡口腔炎病毒（VSV）返回临床前模型，以治疗免疫胜任小鼠中的B16鼠肿瘤。为了增强循环中病毒存活率，我们将使用环磷酰胺（CPA），从而抑制了抗病毒先天/适应性反应，并且应该接受监管机构作为全身病毒疗法的辅助手段。我们已经表明，根据CPA的剂量/时机，高水平的全身病毒可以访问S.C.可以调节肿瘤和毒性以及NAB的水平（控制病毒进入全身组织）。我们还将针对肿瘤脉管系统的主要物理障碍，并表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重大疗法。因此，我们的总体假设是，可以制定临床适用的方案，通过这些方案可以在完全免疫能力的宿主中系统地将肿瘤病毒系统地传递给治疗水平的已建立肿瘤。为了检验这一假设，我们将优化在免疫能力宿主中首次给药后静脉内肿瘤病毒的肿瘤定位/复制（AIM 1）。在特定的目标2和3中，我们将优化静脉内的肿瘤定位/复制。通过修改给药时间，病毒的性质（AIM 2）或宿主免疫系统（AIM 3），使用重复管理的病毒。最后，我们将结合AIMS 1-3的全身传递条件，以治疗良好的皮下和转移性疾病（AIM 4）。这些实验将推动VSV作为梅奥诊所的系统性试验的新试验的开始，以补充我们正在进行的与其他溶瘤病毒的试验。公共卫生相关性：该赠款中的实验旨在提高病毒，专门设计用于破坏癌细胞的效率，可以通过转移（广泛）癌症患者的血液进行。如果成功，它们将导致实施临床试验，以测试这种方法作为一种新型癌症治疗形式的安全性和功效。