Tropism Enhanced Oncolytic Adenovirus for the Treatment of Brain Tumors

用于治疗脑肿瘤的趋向性增强溶瘤腺病毒

• 批准号: 9128419
• 负责人: Juan Fueyo
• 金额: $ 28.96万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9128419
• 关键词: Adenoviruses; Affect; Aftercare; Autophagocytosis; Biological; Bone Marrow; Brain Neoplasms; Cell Death; Cell model; Cells; Clinic; Clinical; Clinical Trials; Cytolysis; Data; Disease; Effectiveness; FDA approved; Fiber; Funding; Genes; Glioblastoma; Glioma; Goals; Grant; Human; In complete remission; Laboratories; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Mesenchymal Stem Cells; Methods; Modeling; Normal Cell; Oncolytic; Oncolytic viruses; Operative Surgical Procedures; Patient-Focused Outcomes; Patients; Phase; Phase I Clinical Trials; RGD (sequence); Recurrence; Role; Safety; Specimen; Stem cells; Testing; Time; Translating; Translations; Tropism; University of Texas M D Anderson Cancer Center; Viral; Virus; arm; base; chemotherapy; clinical application; cohort; effective therapy; glioma cell line; improved; killings; neoplastic cell; next generation; novel; oncolysis; pre-clinical; preclinical study; programs; safety testing; skills; standard care; stem cell therapy; success; temozolomide; tumor

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.

为了改善恶性神经胶质瘤患者的臭名昭著的不良结果，我们开发了一种新颖的 溶瘤腺病毒，Delta-24-RGD。在此孢子赠款的最初资金期间，我们做了 在复发患者中完成第一阶段I期临床试验的重大翻译步骤 恶性神经胶质瘤（NCT00805376）。在此试验中，看到了几个戏剧性的完整回应，并且 对治疗后手术标本的分析首次证明了Delta-24-RGD能够 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。 但是，我们的分析还表明，Delta-24-RGD的功效可以提高1） 增加病毒率，2）改善交付方法。在这种情况下，临床前研究 在我们最初赠款的AIM 2中提出的表明，Delta-24-RGD的疗效是协同的 通过将其与Temozolornide（TMZ）结合来增强。其他观察结果首次表明病毒 介导的自噬和自噬相关的细胞死亡对于脑解析至关重要，促进 自噬可能进一步提高Delta-24-RGD的功效。同样重要的临床前研究 我们最初提案的目标3表明，Delta-24-RGD的交付可以通过使用来提高 血管内施用的骨髓间充质干细胞（BM-HMSCS），装有Delta-24-- RGD。基于这些结果，我们现在假设可以增强Delta-24-RGD的功效 通过将Delta-24-RGD与TMZ相结合，利用自噬和 通过改善BM-HMSC的交付。为了检验这一假设，我们将探索自噬在 使用神经胶质瘤干细胞的TMZ协同作用和病毒性肿瘤，并发展下一代自噬 - 有针对性的溶瘤腺病毒（AIM 1）；评估合并的安全性，功效和生物学效应 在LL/LL临床试验中使用TMZ的Delta-24-RGD（AIM 2），并验证BM-HMSC的有效性 临床前神经胶质瘤干细胞模型和复发性GBM患者的递送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 恶性神经胶质瘤的标准治疗方法。