Enhancing Therapy of Primary and Recurrent Tumors With Systemic Oncolytic Virus

描述（由申请人提供）：我们的总体目标是开发方案，通过该方案可以将溶瘤病毒全身递送到患者体内，从而治疗转移性肿瘤。基于我们的临床前实验，表明静脉内（i. v.）尽管递送溶瘤呼肠孤病毒可以在动物模型中具有显著的抗肿瘤活性，但我们已经完成了I/II期临床试验，证实静脉注射呼肠孤病毒在人体中是安全的。使用来自这些试验的数据，我们另外的临床前实验表明，通过仔细定时的紫杉醇化疗和呼肠孤病毒病毒疗法的组合，可以在静脉内递送后调节肿瘤脉管系统以增加呼肠孤病毒复制，从而导致卡铂/紫杉醇和呼肠孤病毒用于复发性/转移性癌症的I期试验。在本试验的过程中，我们观察到非常令人鼓舞的可能的临床效果的建议，以及出现积极复发的一些患者谁最初反应非常好的治疗后。在本提案中，我们将进一步建立在这些临床前和临床数据的基础上，这些数据累积显示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，当前提议的总体假设是，将有可能开发新的治疗方法，其既改善对静脉内呼肠孤病毒的初始肿瘤应答，又预防或治疗侵袭性肿瘤复发。为了检验这一假设，我们将在病毒免疫/非免疫小鼠中，通过用细胞因子、化疗或放疗（Aim 1）和/或伴侣作用调节宿主，并使用免疫细胞载体保护静脉内施用的呼肠孤病毒（Aim 2），来改善静脉内施用呼肠孤病毒后的初始抗肿瘤应答，以增强递送至肿瘤和/或其脉管系统的病毒的水平和免疫后果。此外，我们将通过靶向一线化疗/病毒疗法治疗失败后出现的可预测复发性肿瘤表型，采用合理的、基于机制的二线疗法治疗初始全身病毒疗法失败的复发性肿瘤（目的3）。总的来说，这些实验将导致新的静脉注射呼肠孤病毒的临床试验，也应该直接适用于一系列不同的肿瘤类型和溶瘤病毒。

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.