Enhancing Therapy of Primary and Recurrent Tumors With Systemic Oncolytic Virus

描述（由申请人提供）：我们的总体目标是制定方案，通过该方案，溶瘤病毒可以系统地传递给患者，从而治疗转移性肿瘤。基于我们的临床前实验显示，在动物模型中静脉注射溶瘤呼肠孤病毒具有显著的抗肿瘤活性，我们已经完成了I/II期临床试验，确认静脉注射呼肠孤病毒在人类中是安全的。利用这些试验的数据，我们的其他临床前实验表明，通过精心定时的紫杉醇化疗和呼肠孤病毒病毒治疗联合静脉给药，肿瘤血管系统可以调节呼肠孤病毒复制的增加，从而导致卡铂/紫杉醇和呼肠孤病毒治疗复发/转移性癌症的I期试验。在这项试验的过程中，我们观察到非常令人鼓舞的可能的临床效果的建议，以及在一些患者中出现侵袭性复发，这些患者最初在治疗后反应非常好。在目前的提案中，我们将进一步建立这些临床前和临床数据，这些数据累积表明PAC/Reo是一种耐受性良好且潜在有效的向肿瘤患者提供溶瘤病毒治疗的方法。因此，当前建议的总体假设是，有可能开发出新的治疗方法，既能改善静脉呼肠孤病毒对肿瘤的初始反应，又能预防或治疗侵袭性肿瘤复发。为了验证这一假设，我们将在病毒免疫/非免疫小鼠中，通过使用细胞因子、化学或放射治疗（Aim 1）和/或陪伴和保护宿主，通过免疫细胞载体（Aim 2）来改善呼肠孤病毒静脉注射后的初始抗肿瘤反应，以提高病毒递送到肿瘤和/或其脉管系统的水平和免疫后果。此外，我们将针对一线化疗/病毒治疗失败后出现的可预测的复发肿瘤表型，采用合理的、基于机制的二线治疗来治疗初始全身病毒治疗失败的复发肿瘤（目标3）。总的来说，这些实验将导致静脉注射呼肠孤病毒的新的临床试验，也应该直接适用于不同类型的肿瘤和溶瘤病毒。

DESCRIPTION (provided by applicant): Our overall goal is to develop protocols by which oncolytic viruses can be systemically delivered in patients leading to treatment of metastatic tumors. Based upon our pre-clinical experiments showing that intravenous (i.v.) delivery of oncolytic reovirus can have significant anti tumor activity in animal models, we have completed Phase I/II clinical trials, confirming that i.v. reovirus is safe in humans. Using data from these trials, our additional pre-clinical experiments showed that tumor vasculature can be conditioned for increased reovirus replication following i.v. delivery by carefully timed combination of paclitaxel chemotherapy and reovirus virotherapy, leading to a Phase I trial of carboplatin/paclitaxel and reovirus for relapsed/metastatic cancers. During the course of this trial, we observed very encouraging suggestions of possible clinical effects, as well as the emergence of aggressive recurrences in some patients who initially responded very well following the therapy. In the current proposal, we will build further on these pre-clinical and clinical data, which have, cumulatively, shown that PAC/Reo is a well tolerated, and potentially efficacious, method of deliverying oncolytic virotherapy to tumor bearing patients. Therefore, the overall hypothesis of the current proposal is that it will be possible to develop novel treatments which both improve initial tumor responses to i.v. reovirus and either prevent, or treat, aggressive tumor recurrences. To test this hypothesis, we will improve initial anti tumor responses following i.v. reovirus, in virus immune/ non-immune mice, by conditioning the host with cytokines, chemo- or radio-therapy (Aim 1) and/or chaperoning, and protecting, i.v. administered reovirus using immune cell carriers (Aim 2), in order to enhance levels, and immune consequences, of virus delivered to the tumor and/or its vasculature. In addition, we will treat recurrent tumors, which fail initial systemic virotherapy, with rational, mechanism-based 2nd line therapies by targeting the predictable recurrent tumor phenotype which emerges upon treatment failure with front line chemo-/virotherapy (Aim 3). Overall these experiments will lead to new clinical trials for i.v. delivery of reovirus and should also be directly applicable to a rage of both different tumor types and oncolytic viruses.