Enhancing Systemic Delivery of Oncolytic Viruses for Cancer Therapy

摘要 溶瘤病毒治疗的一个主要目标是全身递送到转移性疾病。不过，目前， 静脉注射。病毒不能在足够的水平上访问肿瘤以实现消退(S)。因此，新的协议 必须开发出病毒可以在循环中存活足够长的时间来进入肿瘤 面对抗病毒中和抗体(NAB)，循环中的成分使 病毒，以及防止血管外循环的血管屏障。在我们的全身一期临床试验中 随着呼肠孤病毒的传播，有令人鼓舞的证据表明病毒到达了转移性肿瘤。我们现在就会 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。为了增强病毒在循环中的存活率，我们将使用环磷酰胺 (CPA)，它抑制抗病毒的先天/适应性反应，应该是监管机构可以接受的 当局将其作为系统性病毒治疗的辅助手段。我们已经证明，这取决于剂量/时机 在CPA中，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 (它控制病毒进入全身组织)，是可以调节的。我们也会瞄准少校 肿瘤血管的物理屏障，并已表明诱导血管通透性 安全地促进循环病毒进入肿瘤以及重要的治疗。因此，我们的 总的假设是，将有可能开发出临床适用的方案，通过 溶瘤病毒可以在治疗水平上以系统的方式传递到已建立的肿瘤中，完全 免疫能力强的宿主。为了验证这一假设，我们将优化肿瘤的定位/复制 在具有免疫能力的宿主中首次接种后静脉注射溶瘤病毒(目标1)。在……里面 具体目标2和3，我们将优化静脉注射的肿瘤定位/复制。使用重复功能的病毒 通过修改给药时间、病毒性质(目标2)或宿主进行管理 免疫系统(目标3)。最后，我们将结合系统交付的最佳条件 目标1-3，用于治疗公认的皮下和转移疾病(目标4)。这些实验 将推动在梅奥诊所启动VSV作为系统性药物的新试验，以补充我们的 正在进行与其他溶瘤病毒的试验。

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.