Enhancing Systemic Delivery of Oncolytic Viruses for Cancer Therapy

描述（由申请人提供）：溶瘤病毒治疗的主要目标是转移性疾病的全身递送。然而，目前，静脉注射病毒不能达到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）的情况下进入肿瘤，NAb是循环中灭活病毒的成分，并且血管屏障可以防止额外的血管破坏。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，使用水疱性口炎病毒（VSV）在免疫能力强的小鼠中治疗B16小鼠肿瘤。为了提高病毒在循环中的存活，我们将使用环磷酰胺（CPA），它可以抑制抗病毒的先天/适应性反应，并且应该被监管当局接受作为全身病毒治疗的辅助药物。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sc肿瘤并产生毒性，并且NAb（控制病毒进入全身性组织）的水平可以被调节。我们还将针对肿瘤血管系统的主要物理屏障，并已表明，诱导血管通透性可以安全促进循环病毒进入肿瘤，并提供重要的治疗。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能力的宿主中系统地递送到已建立的肿瘤，达到治疗水平。为了验证这一假设，我们将优化首次给药后静脉溶瘤病毒在免疫能力强的宿主体内的肿瘤定位/复制（目的1）。在特定目标2和3中，我们将通过修改给药时间、病毒的性质（目标2）或宿主免疫系统（目标3），通过重复给药来优化静脉注射病毒的肿瘤定位/复制。最后，我们将结合Aims 1-3系统递送的最佳条件来治疗已建立的皮下和转移性疾病（Aim 4）。这些实验将推动梅奥诊所启动VSV作为系统性药物的新试验，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，这种病毒是专门用于破坏癌细胞的，可以通过转移性（广泛）癌症患者的血液输送。如果成功，他们将引导临床试验的实施，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.