Assessment of YB-1 Dependent Oncolytic Adenovirus-Based Glioma-Virotherapy on Cellular Immune Responses

YB-1 依赖性溶瘤腺病毒胶质瘤病毒疗法对细胞免疫反应的评估

• 批准号: 390152390
• 负责人: Professor Dr. Per Sonne Holm
• 金额: --
• 依托单位: Universitätsklinik für Mund-, Kiefer- und Gesichtschirurgie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/390152390?language=en
• 关键词: Assessment; YB; Dependent; Oncolytic; Adenovirus

Glioblastoma (GBM) is the most common malignant brain tumors. Although surgical resection, radiotherapy as well as chemotherapy prolong survival to 12-15 months, new therapeutic strategies areneeded. Oncolytic virotherapy is an upcoming therapy strategy for cancer treatment. A variety of preclinical and clinical trials have shown that adenoviruses can be used as potent agents in the treatment of cancer. In addition, recent reports have presented strong evidence for a significant role of oncolytic virotherapy in the activation of anti-tumor immune responses. With regard to oncolytic adenoviruses (OAV) we have demonstrated that YB-1 is a potent factor we have used to develop YB-1-dependent OAVs (YB-1-OAV) showing the capacity of tumor-selective replication and convincing oncolytic property in different murine xenograft tumor models. In recent years we focused on the optimization of viral properties to increase its immunogenic activity to elicit a potent antitumor immune response. Our newly developed YB-1-OAVs facilitate a highly immunogenic kind of cell death. This is an advantage to virothera-peutic strategies based on Adeno-WT-derived OAV which evolutionary inhibit immune response. However, little is known about the effect of OAV mediated cell killing and its specific effects on the immune system in vitro and in vivo. YB-1 OAVs give us the unique opportunity to investigate the role of the immune system to elicit a potent antitumor immune response. Therefore, in the planned project we want to investigate the anti-tumoral immune activation by YB-1-OAV based virotherapy and ist impact on the therapeutic efficacy in vitro in human GBM specimen and in an in vivo humanized murine GBM model. Combined viro-/immunotherapy for GBM, even after enhancement by immunogenic YB-1-OAVs, might not yet achieved its full potential. One reason is that glioma have developed an array of strategies to evade and suppress antitumor immune responses. PD-1 is an immune checkpoint receptor that is expressed on lymphocytes and has been implicated to be a mediator of immune suppression in a variety of tumors, including GBM. Binding of PD-1 to its ligand PD-L1, which is expressed on GBM cells, induces exhaustion of tumor infiltrating T cells. Blocking this interaction has been shown to enhance the immune response towards GBM and to prolongate, in combination with radiotherapy, median survival of GBM bearing mice. Therefore, in a second step it is planned to combine YB1-OAV-virotherapy with the blockade of PD-1/PD-L1 signaling (by either applying Nivolumab or by virus-based expressing of a PD-L1 neutralizing anibody directly in infected glioma cells in the tumor micromilieu, and to analyze whether this will further enhance the therapeutic effects of anti-GBM virotherapy. Final goal is the development of a novel therapy for recurrent GBM by combining oncoviro- and immunoherapeutic approaches.

胶质母细胞瘤（GBM）是最常见的恶性脑肿瘤。虽然手术切除、放疗和化疗可使生存期延长至12-15个月，但仍需要新的治疗策略。溶瘤病毒疗法是一种即将到来的癌症治疗策略。各种临床前和临床试验表明，腺病毒可用作治疗癌症的有效药物。此外，最近的报道已经提供了溶瘤病毒疗法在激活抗肿瘤免疫应答中的重要作用的有力证据。关于溶瘤腺病毒（OAV），我们已经证明YB-1是我们已经用于开发YB-1依赖性OAV（YB-1-OAV）的有效因子，其在不同的鼠异种移植肿瘤模型中显示肿瘤选择性复制的能力和令人信服的溶瘤性质。近年来，我们专注于优化病毒特性，以增加其免疫原性活性，从而引发有效的抗肿瘤免疫应答。我们新开发的YB-1-OAV促进了一种高度免疫原性的细胞死亡。这是基于腺病毒WT衍生的OAV的病毒治疗策略的优势，其进化抑制免疫应答。然而，关于OAV介导的细胞杀伤作用及其在体外和体内对免疫系统的特异性作用知之甚少。YB-1 OAV为我们提供了独特的机会来研究免疫系统的作用，以引发有效的抗肿瘤免疫应答。因此，在计划的项目中，我们想要研究基于YB-1-OAV的病毒疗法的抗肿瘤免疫激活及其对体外人GBM标本和体内人源化鼠GBM模型中的治疗功效的影响。GBM的联合病毒/免疫疗法，即使在免疫原性YB-1-OAV增强后，可能尚未实现其全部潜力。其中一个原因是胶质瘤已经发展出一系列策略来逃避和抑制抗肿瘤免疫反应。PD-1是一种免疫检查点受体，在淋巴细胞上表达，并被认为是多种肿瘤（包括GBM）中免疫抑制的介质。PD-1与其在GBM细胞上表达的配体PD-L1的结合诱导肿瘤浸润性T细胞的耗竭。阻断这种相互作用已经显示出增强对GBM的免疫应答，并且与放射疗法组合，提高携带GBM的小鼠的中值存活率。因此，在第二步中，计划将联合收割机YB 1-OV-病毒疗法与PD-1/PD-L1信号传导的阻断（通过应用纳武单抗或通过直接在肿瘤微环境中的感染的神经胶质瘤细胞中基于病毒表达PD-L1中和抗体）组合，并分析这是否将进一步增强抗GBM病毒疗法的治疗效果。最终的目标是通过结合肿瘤病毒和免疫疗法开发一种新的治疗复发性GBM的方法。