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

由生物标志物驱动的 DB107（一种逆转录病毒复制载体）与 5-FC 联合治疗复发性胶质母细胞瘤或间变性星形细胞瘤患者的 2 期研究

• 批准号: 10722246
• 负责人: Ashish Harish Shah
• 金额: $ 17.94万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-14 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722246
• 关键词: Adjuvant Therapy; Adult; Aftercare; Anaplastic astrocytoma; Attention; Biological Products; Biopsy; Blood; Blood specimen; Bystander Effect; CD8-Positive T-Lymphocytes; Cell Nucleus; Clinical; Clinical Trials; Complex; Cytosine deaminase; Disease; E-Selectin; Enzyme-Linked Immunosorbent Assay; Excision; Exposure to; Flucytosine; Fluorouracil; Foundations; Genes; Genotype; Glioblastoma; Glioma; Goals; Immune; Immune response; Immunocompetent; Immunophenotyping; Infiltration; Interferon Activation; Interferon Type II; Interleukin-6; Intravenous; Isocitrate Dehydrogenase; Mediating; Modality; Modeling; Myeloid-derived suppressor cells; Names; Normal Cell; Patients; Phase; Phase III Clinical Trials; Primary Brain Neoplasms; Prodrugs; Prognosis; Prognostic Marker; Progression-Free Survivals; RNA; Recurrence; Resectable; Serum; Single Nucleotide Polymorphism; Survival Rate; T cell infiltration; T cell response; TNF gene; Therapeutic; Time; Transgenes; Tumor Immunity; Untranslated RNA; Viral; Virotherapy; Virus; anti-tumor immune response; biomarker driven; biomarker identification; chemoradiation; chemotherapy; clinical candidate; clinical translation; cytokine; digital; efficacy evaluation; gene therapy; hazard; improved; improved outcome; in vivo; mutant; mutational status; neoplastic cell; neuro-oncology; novel marker; patient prognosis; patient stratification; patient subsets; phase III trial; prospective; public health relevance; randomized, clinical trials; recruit; responders and non-responders; response; secondary endpoint; single nucleus RNA-sequencing; standard care; standard of care; transcriptomics; tumor; vector

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.

项目摘要 高级别胶质瘤是成人中最常见的原发性脑肿瘤， 尽管进行了最大程度的安全切除和放化疗，但中位5年生存率。在过去的20年里， 高级别神经胶质瘤的标准治疗方法没有显著变化;因此，注意力已经转移到 开发病毒疗法来改善这种致命疾病的结果。优选基于病毒的基因疗法 选择性地将转基因递送到肿瘤细胞并且在正常细胞中是不允许的生物制剂。的 第一个临床候选逆转录病毒复制载体（RRV）（DB 107，vocimagene amiretrorepvec）递送一种 转基因，胞嘧啶脱氨酶，将无毒的前药5-氟胞嘧啶（5-FC）转化为细胞内的 化疗药物5-氟尿嘧啶最近，III期随机临床试验（Toca 5，NCT 02414165）使用 第一个临床候选者DB 107（以前命名为Toca 511）在选择的 具有新型生物标志物DGM 7的患者亚组与仅接受标准治疗的患者（SOC）的比较 (18.3对比12.0个月，HR：0.5，p<0.0167）。由于DGM 7高度预测对逆转录病毒的阳性反应， 基因治疗，我们正在进行第二阶段，生物标志物驱动的试验，以先验确定“反应者”DB 107 +5- 的fc此外，我们之前已经证明DB 107 +5-FC抑制髓源性抑制细胞， 募集肿瘤浸润性CD 8 + T细胞。因此，我们假设DB 107 +5-FC不仅可以改善 结果复发性高级别胶质瘤患者，但也将诱导强大的抗肿瘤免疫 反应为了非侵入性地表征免疫应答，我们计划采用多重免疫ELISA 在暴露于DB 107 +5-FC之前和之后的治疗患者中。此外，我们将验证这些在体内免疫- 用离体HGG的单核RNA-seq的ELISA特征。本研究的基本目标是：（1） 前瞻性验证DGM 7作为一种新的生物标志物，以识别对DB 107有反应的患者，以及2） 全面表征基于病毒的基因治疗后的抗肿瘤免疫应答， 基于ELISA和转录组学方法。拟议的临床试验不仅可以验证临床DGM 7作为 DB 107是复发性高级别胶质瘤的预后标志物，也为临床治疗奠定了基础。 生物标志物驱动的神经肿瘤学临床试验的翻译。