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
基本信息
- 批准号:10722246
- 负责人:
- 金额:$ 17.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Adjuvant TherapyAdultAftercareAnaplastic astrocytomaAttentionBiological ProductsBiopsyBloodBlood specimenBystander EffectCD8-Positive T-LymphocytesCell NucleusClinicalClinical TrialsComplexCytosine deaminaseDiseaseE-SelectinEnzyme-Linked Immunosorbent AssayExcisionExposure toFlucytosineFluorouracilFoundationsGenesGenotypeGlioblastomaGliomaGoalsImmuneImmune responseImmunocompetentImmunophenotypingInfiltrationInterferon ActivationInterferon Type IIInterleukin-6IntravenousIsocitrate DehydrogenaseMediatingModalityModelingMyeloid-derived suppressor cellsNamesNormal CellPatientsPhasePhase III Clinical TrialsPrimary Brain NeoplasmsProdrugsPrognosisPrognostic MarkerProgression-Free SurvivalsRNARecurrenceResectableSerumSingle Nucleotide PolymorphismSurvival RateT cell infiltrationT cell responseTNF geneTherapeuticTimeTransgenesTumor ImmunityUntranslated RNAViralVirotherapyVirusanti-tumor immune responsebiomarker drivenbiomarker identificationchemoradiationchemotherapyclinical candidateclinical translationcytokinedigitalefficacy evaluationgene therapyhazardimprovedimproved outcomein vivomutantmutational statusneoplastic cellneuro-oncologynovel markerpatient prognosispatient stratificationpatient subsetsphase III trialprospectivepublic health relevancerandomized, clinical trialsrecruitresponders and non-respondersresponsesecondary endpointsingle nucleus RNA-sequencingstandard carestandard of caretranscriptomicstumorvector
项目摘要
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
项目成果
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