Enhancing Systemic Delivery of Oncolytic Viruses for Cancer Therapy

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，静脉注射病毒不能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，通过该方案，病毒可以在循环中存活足够长的时间，以在抗病毒中和抗体（NAb）、抵抗病毒的循环组分和防止外渗的血管屏障的情况下接近肿瘤。在我们的呼肠孤病毒全身递送的I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。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）治疗免疫活性小鼠中的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），其抑制抗病毒先天性/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治疗。我们已经表明，根据CPA的剂量/时间，高水平的全身性病毒可以进入s.c.可以调节NAb的毒性和水平（其控制病毒进入全身组织）。我们还将靶向肿瘤血管系统的主要物理屏障，并且已经表明诱导血管通透性安全地促进循环病毒进入肿瘤沿着显著的治疗。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，溶瘤病毒可以在完全免疫活性宿主中以治疗水平全身递送至已建立的肿瘤。为了检验这一假设，我们将在免疫活性宿主中首次给药后优化静脉内溶瘤病毒的肿瘤定位/复制（目的1）。在特定目的2和3中，我们将通过修改给药时间、病毒性质（目的2）或宿主免疫系统（目的3），使用重复给药优化i. v.病毒的肿瘤定位/复制。最后，我们将联合收割机结合目标1-3的全身递送的最佳条件来治疗已确定的皮下和转移性疾病（目标4）。这些实验将推动在马约诊所启动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。公共卫生相关性：这项资助的实验旨在提高病毒的效率，这些病毒专门设计用于破坏癌细胞，可以通过转移性（广泛）癌症患者的血流输送。如果成功，他们将导致临床试验的实施，以测试这种方法作为一种新的癌症治疗形式的安全性和有效性。

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.