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

项目1：基于神经干细胞的恶性胶质瘤溶瘤病毒疗法

基本信息

批准号：
10478872
负责人：
MACIEJ S LESNIAK
金额：
$ 27.85万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-17 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10478872
关键词：
Adenovirus Vector Adult Advisory Committees Antitumor Response Attenuated Beds Binding Biopsy Blood Circulation Brain CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Capsid Cells Characteristics Chemotherapy and/or radiation Clinical Clinical Trials Disease Dose Enrollment Excision Exhibits Gadolinium Genetic Engineering Genetic Transcription Glioblastoma Glioma Goals Human IL6 gene IL8 gene Image Immune Immune response Injections Interferon Type II Investigational Drugs Investigational New Drug Application Iron Label Liquid substance Location Magnetic Resonance Imaging Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Modality Modification Molecular Monitor Mus Natural Killer Cells Neuraxis Newly Diagnosed Oncolytic Oncolytic viruses Patients Phase I Clinical Trials Positioning Attribute Pre-Clinical Model Predisposition Promoter Regions Quantitative Reverse Transcriptase PCR Radiation therapy Recombinant DNA Recovery Recurrence Resectable Residual Tumors Safety Secure Site Slice Specificity Therapeutic Translating Treatment Efficacy Tumor Subtype United States Food and Drug Administration Unresectable Viral Virus Virus Diseases Virus Receptors Virus Replication Work Xenograft Model Xenograft procedure base cancer cell cancer therapy conditionally replicative adenovirus cytokine evidence base immunological status meetings migration neoplastic cell nerve stem cell novel novel therapeutics oncolytic adenovirus oncolytic virotherapy particle peripheral blood pre-clinical preclinical study response stem cells survivin synergism therapy outcome translational approach treatment group treatment strategy tumor tumor diagnosis vector

项目摘要

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. !

项目 1：项目摘要溶瘤病毒疗法（OV）是一种新型的抗癌疗法，包括使用基因工程条件复制病毒可以瞄准并摧毁癌细胞。这样的选择性病毒复制是通过采用各种策略来实现的，包括转录靶向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。我们课题组研发出双靶向溶瘤腺病毒载体 CARd-Survivin-pK7 (CARd-S-pk7) 并广泛评估了该载体用于治疗恶性临床前环境中的神经胶质瘤。在这种情况下，CRAd-S-pk7 在小鼠中表现出广泛的抗肿瘤活性携带颅内人类神经胶质瘤异种移植物，包括高度侵袭性的 CD133+ 神经胶质瘤干细胞衍生的异种移植模型并与传统的抗神经胶质瘤化疗和放疗配合。 OV 的主要局限性之一是瘤内分布较差。为了解决这个问题我们小组已经证明神经干细胞（NSC）可以用作细胞载体来增强病毒递送。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，从而导致比单独局部递送治疗病毒具有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。我们已完成 FDA 指示的所有工作临床前研究，与食品药品监督管理局召开新药研究前（IND）会议 (FDA) 并完成了确保 I 期临床试验 IND 的所有必要步骤。此举的目标 SPORE项目是在I期临床试验中评估NSCs-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标 1：评估施用 CRAd-S-pK7 负载 NSC 的患者的临床反应。具体目标 2：研究接受携带 CRAd-S-pK7 的 NSC 的患者的免疫反应。具体目标 3：基于影像的 NSCs-CRAd-S-pK7 后 NSC 分布和肿瘤反应的证据治疗。！