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.

项目总结