Tropism Enhanced Oncolytic Adenovirus for the Treatment of Brain Tumors

为了改善恶性胶质瘤患者臭名昭著的不良预后，我们开发了一种新的 溶瘤腺病毒，Delta-24-RGD。在这笔孢子赠款的最初资助期，我们做出了 在复发患者中完成首个人类I期临床试验的重大转化性步骤 恶性胶质瘤(NCT00805376)。在这场试验中，我们看到了几个戏剧性的完整反应，以及 对治疗后手术标本的分析首次证明Delta-24-RGD能够 复制和杀死人类肿瘤细胞，强调迫切需要进一步发展这一方法。 然而，我们的分析也表明Delta-24-RGD的疗效可以提高1) 加大病毒传播，2)改进投放方式。在此背景下，临床前研究 在我们最初拨款的目标2中提出的建议表明Delta-24-RGD的疗效是协同的 与替莫唑奈德(TMZ)联合使用可增强疗效。其他观察首次表明，病毒 介导的自噬和自噬相关的细胞死亡是肿瘤分解的关键，而促进 自噬可能进一步提高Delta-24-RGD的疗效。同样重要的是，来自 我们最初提案的目标3表明，Delta-24-RGD的交付可以通过使用 血管内注射Delta-24基因的骨髓间充质干细胞 RGD。基于这些结果，我们现在假设Delta-24-RGD的疗效可以增强 不会通过将Delta-24-RGD与TMZ结合、通过利用自噬以及 通过改善BM-hMSCs的交付。为了验证这一假设，我们将|L：探索自噬在 使用胶质瘤干细胞协同TMZ和病毒溶瘤，并开发下一代自噬- 靶向溶瘤腺病毒(AIM 1)；评估联合治疗的安全性、有效性和生物学效应 Delta24-RGD联合替马西汀A期L/11期临床试验(AIM 2)，并验证BM-hMSCs对 在临床前胶质瘤干细胞模型和复发基底膜患者中传递Delta-24-RGD。这 项目是实现我们将这些病毒和干细胞疗法合法化的长期目标的下一步 恶性胶质瘤的标准治疗。

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.