Project 1: Neural Stem Cell Based Oncolytic Virotherapy of Malignant Glioma

项目1：项目总结 溶瘤病毒疗法(OV)是一种新型的抗癌治疗方法，它包括使用 基因工程有条件地复制病毒，以靶向并摧毁癌细胞。这样的选择性 病毒复制是通过采用各种策略来实现的，其中包括转录靶向哪里的肿瘤 选择性启动子序列用于驱动病毒复制和衣壳修饰，从而促进 治疗性病毒的肿瘤特异性结合。我们团队已经研制出针对溶瘤的双靶向腺病毒 PK7(CARD-S-pk7)，并对其用于治疗恶性肿瘤进行了广泛评价 临床前环境中的胶质瘤。在此条件下，CRAd-S-pk7在小鼠体内表现出广泛的抗肿瘤活性 携带人脑胶质瘤异种移植瘤，包括高度侵袭性的CD133胶质瘤干细胞 衍生的异种移植模型，并配合常规的抗胶质瘤化疗和放射治疗。 OV的主要局限性之一是肿瘤内分布不佳。为了克服这个问题，我们组 已经证明神经干细胞(NSCs)可以作为细胞载体来增强病毒的传递。这 基于载体的OV形式可以增强病毒在肿瘤内的分布和复制，从而导致 比单纯局部注射治疗性病毒更有效的抗肿瘤反应。基于这项工作， 我们现在可以将其转化为临床环境。我们已经完成了FDA指示的所有工作 临床前研究，与食品和药物管理局举行了新药研究前(IND)会议 (FDA)，并完成了获得I期临床试验IND的所有必要步骤。这样做的目的是 孢子计划是在I期临床试验中评价神经干细胞-CRAd-S-PK7作为治疗药物的安全性 恶性胶质瘤患者的平台。我们的具体目标是 具体目的1：评价CRAd-S-pK7负载神经干细胞的临床疗效。 特定目的2：研究携带CRAd-S-pK7基因的神经干细胞移植患者的免疫应答。 特异性靶点3：神经干细胞-CRAd-S-pK7移植后神经干细胞分布和肿瘤反应的影像证据 治疗。 好了！

PROJECT 1: PROJECT SUMMARY Oncolytic virotherapy (OV) is a novel modality of anti-cancer therapy, which consists of using genetically engineered conditionally replicating viruses to target and destroy cancer cells. Such selectivity of viral replication is achieved by employing various strategies including transcriptional targeting where tumor selective promoter sequence is used to drive the virus replication and capsid modifications that can promote tumor specific binding of the therapeutic virus. Our group has developed duel targeted oncolytic adenovirus vector CARd-Survivin-pK7 (CARd-S-pk7) and extensively evaluated this vector for the treatment of malignant glioma in the preclinical setting. In this setting, CRAd-S-pk7 exhibits extensive anti-tumor activity in mice bearing intracranial human glioma xenografts, including the highly aggressive CD133+ glioma stem cell derived xenograft model and cooperates with conventional anti-glioma chemo- and radiotherapy. One of the major limitations of OV is poor intratumoral distribution. To overcome this problem our group has demonstrated that neural stem cells (NSCs) can be used as a cell carrier to enhance viral delivery. This form of carrier based OV can enhance viral distribution as well as replication within the tumor, which results in a much more potent anti-tumor response than local delivery of the therapeutic virus alone. Based on this work, we are now position to translate this into the clinical setting. We have completed all the FDA directed preclinical study, held a pre- Investigational New Drug (IND) meeting with the Food and Drug Administration (FDA) and completed all the necessary steps in securing an IND for a phase I clinical trial. The goal of this SPORE project is to evaluate the safety of NSCs-CRAd-S-pk7 in the phase I clinical trial as a therapeutic platform for patients with malignant glioma. Our specific aims are Specific Aim 1: To evaluate clinical responses in patients administered CRAd-S-pK7-loaded NSCs. Specific Aim 2: To investigate immune response in patients administered NSCs carrying CRAd-S-pK7. Specific Aim 3: Imaging-based evidence of NSC distribution and tumor response after NSCs-CRAd-S-pK7 treatment. !