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，溶瘤病毒可以系统地输送到导致转移性肿瘤治疗的患者中。根据我们的临床前实验表明，静脉(静脉)溶瘤呼肠孤病毒在动物模型中具有显著的抗肿瘤活性，我们已经完成了I/II期临床试验，证实了静脉注射。呼肠孤病毒对人类是安全的。使用这些试验的数据，我们额外的临床前实验表明，静脉注射后肿瘤血管可以被调节以增加呼肠孤病毒的复制。通过谨慎选择紫杉醇化疗和呼肠孤病毒疗法的组合进行给药，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。在这个试验的过程中，我们观察到可能的临床效果的非常令人鼓舞的建议，以及在一些最初治疗后反应非常好的患者中出现积极的复发。在目前的提案中，我们将进一步建立在这些临床前和临床数据的基础上，这些数据已经累积表明，PAC/Reo是一种耐受性很好的、潜在有效的向荷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，将有可能开发出既能改善肿瘤对静脉注射的初始反应的新疗法。呼肠孤病毒和预防或治疗侵袭性肿瘤复发。为了验证这一假设，我们将在静脉注射后改善最初的抗肿瘤反应。呼肠孤病毒，在病毒免疫/非免疫小鼠中，通过用细胞因子、化疗或放射治疗(目标1)和/或陪伴和保护静脉注射来调节宿主。使用免疫细胞载体注射呼肠孤病毒(AIM 2)，以提高运送到肿瘤和/或其血管系统的病毒水平和免疫后果。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，用合理的、基于机制的二线治疗来治疗最初全身病毒治疗失败的复发肿瘤(目标3)。总体而言，这些实验将导致新的静脉注射临床试验。呼肠孤病毒的传递，也应该直接适用于各种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.