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.

摘要 溶瘤病毒疗法的主要目标是全身递送至转移性疾病。但是目前， 静脉注射病毒不能以足够的水平进入肿瘤以实现消退。因此，新的协议 必须开发病毒可以在循环中存活足够长的时间以进入肿瘤， 面对抗病毒中和抗体（NAb），循环的组成部分， 病毒和防止外渗的血管屏障。在我们的I期临床试验中， 通过呼肠孤病毒的递送，存在病毒到达转移性肿瘤的令人鼓舞的证据。我们现在将 回到我们的临床前模型，使用水泡性口炎病毒（VSV）治疗B16小鼠肿瘤， 免疫能力强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)，其抑制抗病毒先天/适应性反应，并且应该是监管机构可接受的。 作为系统性病毒治疗的辅助手段。我们已经证明，根据剂量/时间 的CPA，高水平的系统性病毒可以进入s.c.肿瘤和毒性，以及NAb水平 （其控制病毒进入全身组织），可以被调节。我们还将针对 并且已经显示血管渗透性的诱导 安全地促进循环病毒进入肿瘤沿着显著的治疗。所以我们的 总体假设是，有可能制定临床适用的方案， 溶瘤病毒可以以治疗水平，以完全可接受的方式， 免疫能力强的宿主为了验证这一假设，我们将优化肿瘤定位/复制， 在免疫活性宿主中第一次给药后静脉内溶瘤病毒（Aim 1）。在 具体目标2和3，我们将使用重复序列优化i. v.病毒的肿瘤定位/复制 通过改变给药时间、病毒的性质（目的2）或宿主， 免疫系统（目标3）。最后，我们将结合联合收割机的系统交付的最佳条件， 目的1-3治疗已确定的皮下和转移性疾病（目的4）。这些实验 将推动在马约诊所启动VSV作为全身性药物的新试验，以补充我们的 正在进行的其他溶瘤病毒试验。