A Phase I/II Trial of a Conditionally Replication-competent Adenovirus (Delta-24-rgd) Administered by Convection Enhanced Delivery in Patients With Recurrent Glioblastoma

In the Netherlands a 2 center investigator-driven phase I/II clinical trial is initiated in June 2010 testing the oncolytic adenovirus Delta24-RGD to treat glioblastoma patients. The virus is administrated using convection-enhanced delivery by 4 catheters as delivery technique, targeting solid tumor as well as infiltrated tumor cells within the peri-tumoral brain. Patients will be enrolled in cohorts of 3 per dose-level. The dose levels to be explored are: 10^7, 10^8, 10^9, 10^10, 3*10^10 and 10^11 viral particles (vp). Once the MTD has been determined, or the study has reached the highest dose cohort, a further 6 or 9 patients will be enrolled at the MTD and evaluated for safety and preliminary signs of efficacy, such that in total at least 12 patients have received the MTD.
The primary objective is to determine the safety and tolerability of Delta-24-RGD administered by CED to the tumor and the surrounding infiltrated brain in patients with recurrent GBM. Secondary objectives are to determine the Progression Free Survival (PFS), Overall Survival (OS), and tumor response rate in patients with recurring tumors amenable for surgical resection and treated at the MTD.
Cerebrospinal fluid as well as brain interstitial fluid by microdialysis next to the routinely collected samples of blood at various timepoints before, during and after virus infusion. Various neurodegenerative biomarkers as well as markers of immune response will be assessed in these samples.
Furthermore extensive sampling and PCR analyses will be performed to evaluate distribution and shedding of the virus.

开始日期2010-06-01

申办/合作机构

Erasmus MC

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100 项与 delta-24-RGD adenovirus(Erasmus Medical Center) 相关的临床结果

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100 项与 delta-24-RGD adenovirus(Erasmus Medical Center) 相关的专利（医药）

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项与 delta-24-RGD adenovirus(Erasmus Medical Center) 相关的文献（医药）

2024-08-05·Neuro-Oncology

The oncolytic adenovirus Delta-24-RGD in combination with ONC201 induces a potent antitumor response in pediatric high-grade and diffuse midline glioma models

Article

作者: Alonso, Marta M ; Gonzalez-Huarriz, Marisol ; Hernaez, Mikel ; Ochoa, Maria C ; Hervás-Corpión, Irati ; van der Lugt, Jasper ; Venneti, Sriram ; Dhandapani, Laasya ; Koschmann, Carl ; Phoenix, Timothy N ; Allen, Joshua E ; Tallon-Cobos, Antonio Carlos ; Dun, Matthew D ; Fueyo, Juan ; Hernandez-Osuna, Reyes ; Gomez-Manzano, Candelaria ; Nazarian, Javad ; Becher, Oren J ; Gallego Perez-Larraya, Jaime ; Patiño-García, Ana ; Marrodan, Lucía ; Lacalle, Andrea ; Laspidea, Virginia ; García-Moure, Marc ; Guruceaga, Elizabeth ; Mueller, Sabine ; Zalacain, Marta ; Marco-Sanz, Javier ; Casares, Noelia ; Labiano, Sara ; Ausejo-Mauleon, Iker ; de la Nava, Daniel

AbstractBackgroundPediatric high-grade gliomas (pHGGs), including diffuse midline gliomas (DMGs), are aggressive pediatric tumors with one of the poorest prognoses. Delta-24-RGD and ONC201 have shown promising efficacy as single agents for these tumors. However, the combination of both agents has not been evaluated.MethodsThe production of functional viruses was assessed by immunoblotting and replication assays. The antitumor effect was evaluated in a panel of human and murine pHGG and DMG cell lines. RNAseq, the seahorse stress test, mitochondrial DNA content, and γH2A.X immunofluorescence were used to perform mechanistic studies. Mouse models of both diseases were used to assess the efficacy of the combination in vivo. The tumor immune microenvironment was evaluated using flow cytometry, RNAseq, and multiplexed immunofluorescence staining.ResultsThe Delta-24-RGD/ONC201 combination did not affect the virus replication capability in human pHGG and DMG models in vitro. Cytotoxicity analysis showed that the combination treatment was either synergistic or additive. Mechanistically, the combination treatment increased nuclear DNA damage and maintained the metabolic perturbation and mitochondrial damage caused by each agent alone. Delta-24-RGD/ONC201 cotreatment extended the overall survival of mice implanted with human and murine pHGG and DMG cells, independent of H3 mutation status and location. Finally, combination treatment in murine DMG models revealed a reshaping of the tumor microenvironment to a proinflammatory phenotype.ConclusionsThe Delta-24-RGD/ONC201 combination improved the efficacy compared to each agent alone in in vitro and in vivo models by potentiating nuclear DNA damage and in turn improving the antitumor (immune) response to each agent alone.

2024-03-01·Molecular Therapy

Chimeric oncolytic adenovirus evades neutralizing antibodies from human patients and exhibits enhanced anti-glioma efficacy in immunized mice

Article

作者: Fueyo, Juan ; Fan, Xuejun ; Kim, Debora ; Ene, Chibawanye I ; Lang, Frederick F ; Lopez-Rivas, Andres R ; Gumin, Joy ; Singh, Sanjay K ; Sohoni, Sagar S ; Nguyen, Teresa T ; Gomez-Manzano, Candelaria ; Alonso, Marta M ; Jiang, Hong ; Parthasarathy, Akhila ; Shin, Dong Ho ; Gillard, Andrew G

Oncolytic viruses are a promising treatment for patients with high-grade gliomas, but neutralizing antibodies can limit their efficacy in patients with prior virus exposure or upon repeated virus injections. Data from a previous clinical trial using the oncolytic adenovirus Delta-24-RGD showed that generation of anti-viral neutralizing antibodies may affect the long-term survival of glioma patients. Past studies have examined the effects of neutralizing antibodies during systemic virus injections, but largely overlooked their impact during local virus injections into the brain. We found that immunoglobulins colocalized with viral proteins upon local oncolytic virotherapy of brain tumors, warranting a strategy to prevent virus neutralization and maximize oncolysis. Thus, we generated a chimeric virus, Delta-24-RGD-H43m, by replacing the capsid protein HVRs from the serotype 5-based Delta-24-RGD with those from the rare serotype 43. Delta-24-RGD-H43m evaded neutralizing anti-Ad5 antibodies and conferred a higher rate of long-term survival than Delta-24-RGD in glioma-bearing mice. Importantly, Delta-24-RGD-H43m activity was significantly more resistant to neutralizing antibodies present in sera of glioma patients treated with Delta-24-RGD during a phase 1 clinical trial. These findings provide a framework for a novel treatment of glioma patients that have developed immunity against Delta-24-RGD.

2024-03-01·Molecular Therapy: Oncology

Gut microbiota composition is associated with the efficacy of Delta-24-RGDOX in malignant gliomas

Article

作者: Meléndez-Vázquez, Natalie M ; Fueyo, Juan ; Nguyen, Teresa T ; Godoy-Vitorino, Filipa ; Fan, Xuejun ; López-Rivas, Andrés R ; Gomez-Manzano, Candelaria

Glioblastoma, the most common primary brain tumor, has a 6.8% survival rate 5 years post diagnosis. Our team developed an oncolytic adenovirus with an OX-40L expression cassette named Delta-24-RGDOX. While studies have revealed the interaction between the gut microbiota and immunotherapy agents, there are no studies linking the gut microbiota with viroimmunotherapy efficacy. We hypothesize that gut bacterial signatures will be associated with oncolytic viral therapy efficacy. To test this hypothesis, we evaluated the changes in gut microbiota in two mouse cohorts: (1) GSC-005 glioblastoma-bearing mice treated orally with indoximod, an immunotherapeutic agent, or with Delta-24-RGDOX by intratumoral injection and (2) a mouse cohort harboring GL261-5 tumors used to mechanistically evaluate the importance of CD4⁺ T cells in relation to viroimmunotherapy efficacy. Microbiota assessment indicated significant differences in the structure of the gut bacterial communities in viroimmunotherapy-treated animals with higher survival compared with control or indoximod-treated animals. Moreover, viroimmunotherapy-treated mice with prolonged survival had a higher abundance of Bifidobacterium. The CD4⁺ T cell depletion was associated with gut dysbiosis, lower mouse survival, and lower antitumor efficacy of the therapy. These findings suggest that microbiota modulation along the gut-glioma axis contributes to the clinical efficacy and patient survival of viroimmunotherapy treated animals.

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适应症	最高研发状态	国家/地区	公司	日期
胶质母细胞瘤	临床2期	荷兰	Erasmus Medical Center (Private Equity)	2010-06-30
复发性胶质母细胞瘤	临床2期	荷兰	Erasmus MC	2010-06-01
转移性乳腺癌	临床前	美国	The University of Texas MD Anderson Cancer Center	2017-07-01