Tropism Enhanced Oncolytic Adenovirus for the Treatment of Brain Tumors

为了改善恶性胶质瘤患者众所周知的不良预后，我们开发了一种新的 溶瘤腺病毒，Delta-24-RGD。在这项SPORE赠款的最初资助期间，我们 在复发性乳腺癌患者中完成首次人体I期临床试验的重要转化步骤 恶性胶质瘤（NCT 00805376）。在该试验中，观察到几种戏剧性的完全反应， 对治疗后手术标本的分析首次证明，Delta-24-RGD能够 在人类肿瘤细胞中复制并杀死人类肿瘤细胞，强调迫切需要进一步发展这种方法。 然而，我们的分析还表明，Delta-24-RGD的疗效可以通过以下方式提高： 增强病毒传播，和2）改进递送方法。在这种情况下，临床前研究 在我们最初资助的目标2中提出的研究表明，Delta-24-RGD的功效是协同的， 与替莫唑胺（TMZ）联合使用。其他观察结果首次表明， 介导的自噬和自噬相关的细胞死亡对溶瘤至关重要， 自噬可以进一步提高Delta-24-RGD的功效。同样重要的是， 我们最初建议的目标3表明，Delta-24-RGD的递送可以通过使用 血管内施用的负载有Delta-24-的骨髓间充质干细胞（BM-hMSC）， RGD。基于这些结果，我们现在假设Delta-24-RGD的功效可以增强 通过将Delta-24-RGD与TMZ组合，通过利用自噬， 通过BM-hMSC改善递送。为了验证这一假设，我们将|l：探讨自噬在细胞凋亡中的作用。 TMZ和使用神经胶质瘤干细胞的病毒溶瘤的协同作用，并开发下一代自噬- 靶向溶瘤腺病毒（Aim 1）;评估联合应用的安全性、疗效和生物学效应 在I/II期临床试验中使用TMZ的Delta-24-RGD（目的2），并验证BM-hMSC对 在临床前胶质瘤干细胞模型和复发性GBM患者中递送Delta-24-RGD。这 该项目是实现我们长期目标的下一步，即使这些病毒和干细胞疗法合法化， 恶性神经胶质瘤的标准治疗。

In order to improve the notoriously poor outcome of patients with malignant glioma, we developed a novel oncolytic adenovirus, Delta-24-RGD. In the initial funding period of this SPORE grant, we made the significant translational step of completing a first-in-human phase I clinical trial in patients with recurrent malignant glioma (NCT00805376). In this trial several dramatic complete responses were seen, and analyses of post treatment surgical specimens proved for the first time that Delta-24-RGD was capable of replicating in and killing human tumor cells, emphasizing the urgent need to further develop this approach. However, our analyses also suggested that the efficacy of Delta-24-RGD could be improved by 1) augmenting viral spread, and 2) improving the method of delivery. In this context, preclinical studies proposed in Aim 2 of our initial grant showed that the efficacy of Delta-24-RGD was synergistically enhanced by combining it with temozolornide (TMZ). Other observations showed for the first time that viral mediated autophagy and autophagy-related cell death are critical to oncolysis, and that promoting autophagy may further improve the efficacy of Delta-24-RGD. Equally important, preclinical studies from Aim 3 of our initial proposal showed that the delivery of Delta-24-RGD could be improved by the use of intravascularly administered bone marrow mesenchymal stem cells (BM-hMSCs) loaded with Delta-24- RGD. Based on these results, we now hypothesize that the efficacy of Delta-24-RGD can be enhanced without adversely affecting safety by combining Delta-24-RGD with TMZ, by harnessing autophagy, and by improving delivery via BM-hMSCs. To test this hypothesis, we wi|l: explore the role of autophagy in the synergy of TMZ and viral oncolysis using glioma stem cells, and develop a next generation autophagy- targeted oncolytic adenovirus (Aim 1); assess the safety, efficacy, and biological effects of combining Delta-24-RGD with TMZ in a phase l/ll clinical trial (Aim 2), and validate the effectiveness of BM-hMSCs to delivery Delta-24-RGD in preclinical glioma stem cell models and in patients with recurrent GBM. This project is the next step in achieving our long-term goal of legitimizing these viral and stem cell therapies as standard treatments of malignant gliomas.