A Phase 2 biomarker driven, Study of DB107, a Retroviral Replicating Vector, Combined With 5-FC in Patients with Recurrent Glioblastoma or Anaplastic Astrocytoma

项目总结 高级别胶质瘤是成人最常见的原发脑瘤，其预后仍较差。 尽管最大限度地安全切除和放化疗，中位5年生存率。在过去的20年里， 高级别胶质瘤的标准治疗方法并没有发生重大变化；因此，注意力已经转移到 开发病毒疗法以改善这种致命疾病的结果。首选以病毒为基础的基因疗法 选择性地将转基因运送到肿瘤细胞的生物制剂，在正常细胞中是不允许的。这个 第一个临床候选逆转录病毒复制载体(RRV)(DB107，vocImagene amiRetrepvec)提供 转基因胞嘧啶脱氨酶，将无毒的前体药物5-氟胞嘧啶(5-FC)转化为细胞内 化疗，5-氟尿嘧啶。最近，第三阶段随机临床试验(TOCA 5，NCT02414165)使用 第一个临床候选DB107(以前被命名为Toca511)在选择的 具有新生物标志物DGM7的患者亚组与单独接受标准护理(SOC)的患者的比较 (18.3vs.12.0个月，HR：0.5p&lt；0.0167)。由于DGM7对逆转录病毒的阳性反应有很高的预测性 基因治疗，我们正在进行一项生物标记物驱动的第二阶段试验，以先验地识别DB107+5- Fc.此外，我们先前已经证明，DB107+5-FC抑制髓系来源的抑制细胞和 招募肿瘤浸润性CD8+T细胞。因此，我们假设DB107+5-FC不仅会改进 复发的高级别胶质瘤患者的预后，但也将诱导强大的抗肿瘤免疫 回应。为了非侵入性地表征免疫反应，我们计划采用多重免疫-elisa。 治疗患者暴露于DB107+5-FC前后。此外，我们将在体内验证这些免疫- HGG体外单核RNA-SEQ酶联免疫吸附试验。这项研究的根本目标是1) 前瞻性地验证DGM7作为一种新的生物标志物来识别对DB107和2有反应的患者) 综合表征病毒基因治疗后的抗肿瘤免疫反应 基于酶联免疫吸附试验和转录本的方法。拟议的临床试验不仅可以验证临床DGM7作为 DB107是复发高级别胶质瘤的预后标志物，但也为临床奠定了基础 神经肿瘤学中生物标记物驱动的临床试验的翻译。

PROJECT SUMMARY High-grade gliomas are the most common primary brain tumors in adults that continue to have poor median 5-year survival rates despite maximal safe resection and chemoradiation. Over the last 20 years, the standard treatment for high-grade gliomas has not changed drastically; therefore, attention has shifted to developing virotherapies to improve outcomes from this lethal disease. Viral based gene therapies are preferred biological agents that selectively deliver transgenes to tumor cells and are not permissible in normal cells. The first clinical candidate retroviral replicating vector (RRV) (DB107, vocimagene amiretrorepvec) delivers a transgene, cytosine deaminase, to convert the non-toxic prodrug 5-fluorocytosine (5-FC) to an intracellular chemotherapeutic, 5-fluorouracil. Recently, phase III randomized clinical trials (Toca 5, NCT02414165) using the first clinical candidate DB107 (formerly named Toca511) demonstrated an improvement in survival in a select subgroup of patients with a novel biomarker, DGM7 compared to patients receiving standard of care alone (SOC) (18.3 vs. 12.0 months, HR: 0.5, p<0.0167). Since DGM7 is highly predictive of a positive response to retroviral gene therapy, we are conducting a Phase II, biomarker-driven trial to a priori identify “responders” to DB107+5- FC. Additionally, we have previously shown that DB107+5-FC suppresses myeloid derived suppressor cells and recruits tumor infiltrating CD8+ T-cells. Therefore, we hypothesize that DB107+5-FC will not only improve outcomes in patients with recurrent high-grade gliomas, but will also induce a robust anti-tumor immune response. To non-invasively characterize the immune response, we plan to employ an multiplex immuno-ELISA in treated patients before and after exposure to DB107+5-FC. Additionally, we will validate these in vivo immuno- ELISA signatures with single-nuclei RNA-seq of HGG ex vivo. The fundamental goal of this study is to 1) prospectively validate DGM7 as a novel biomarker to identify patients who will respond to DB107 and 2) comprehensively characterize the anti-tumor immune response after viral-based gene therapy through serum- based ELISA and transcriptomic approaches. The proposed clinical trial may not only validate clinical DGM7 as a prognostic marker for DB107 in recurrent high-grade gliomas but also set the foundation for the clinical translation of biomarker-driven clinical trials in neuro-oncology.