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

• 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
• 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

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：项目概要 溶瘤病毒疗法（Oncolytic virotherapy，OV）是一种新型的抗肿瘤治疗方法， 基因工程条件复制病毒的目标和破坏癌细胞。这种选择性 病毒复制是通过采用各种策略实现的，包括转录靶向， 选择性启动子序列用于驱动病毒复制和衣壳修饰， 治疗性病毒的肿瘤特异性结合。本课题组研制出双靶向溶瘤腺病毒 载体CARd-Survivin-pK7（CARd-S-pk7），并广泛评价了该载体用于治疗恶性肿瘤的作用。 神经胶质瘤的临床前研究。在这种情况下，CRAd-S-pk7在小鼠中表现出广泛的抗肿瘤活性 携带颅内人胶质瘤异种移植物，包括高度侵袭性CD133+胶质瘤干细胞 衍生的异种移植模型，并与常规的抗胶质瘤化疗和放疗配合。 OV的主要局限之一是肿瘤内分布差。为了解决这个问题，我们的团队 已经证明神经干细胞（NSC）可以用作细胞载体以增强病毒递送。这 基于OV的载体形式可以增强病毒在肿瘤内的分布以及复制，这导致 比单独局部递送治疗性病毒更有效的抗肿瘤反应。在此工作的基础上， 我们现在可以将其转化为临床环境。我们已经完成了所有FDA指示的 临床前研究，与美国食品药品监督管理局（FDA）举行了新药研究前（IND）会议 (FDA)并完成了确保I期临床试验IND的所有必要步骤。这个目标 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。 为恶性胶质瘤患者搭建平台。我们的具体目标是 具体目的1：评价给予负载CRAd-S-pK7的NSC的患者的临床应答。 具体目的2：研究给予携带CRAd-S-pK7的NSC的患者的免疫应答。 具体目标3：NSC分布和NSC-CRAd-S-pK7后肿瘤应答的基于成像的证据 治疗 !