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

2024-06-01·Molecular Therapy: Oncology

The heterogeneous sensitivity of pediatric brain tumors to different oncolytic viruses is predicted by unique gene expression profiles

Article

作者: Vazaios, Konstantinos ; Alonso, Marta M ; Hulleman, Esther ; Meel, Michaël H ; Hoeben, Rob C ; Metselaar, Dennis S ; Lamfers, Martine L M ; van den Hoogen, Bernadette G ; Hoeben, Rob C. ; Chiocca, E. Antonio ; Vogelezang, Lisette B. ; Goins, William F ; Calkoen, Friso G ; Li, Yunlei ; Stubbs, Andrew ; van den Hoogen, Bernadette G. ; van der Lugt, Jasper ; Alonso, Marta M. ; Chiocca, E Antonio ; Metselaar, Dennis S. ; Meel, Michaël H. ; Ju, Jie ; Goins, William F. ; Kemp, Vera ; Calkoen, Friso G. ; Vogelezang, Lisette B ; Waranecki, Piotr ; Stavrakaki, Εftychia ; Lamfers, Martine L.M.

Despite decades of research, the prognosis of high-grade pediatric brain tumors (PBTs) remains dismal; however, recent cases of favorable clinical responses were documented in clinical trials using oncolytic viruses (OVs). In the current study, we employed four different species of OVs: adenovirus Delta24-RGD, herpes simplex virus rQNestin34.5v1, reovirus R124, and the non-virulent Newcastle disease virus rNDV-F0-GFP against three entities of PBTs (high-grade gliomas, atypical teratoid/rhabdoid tumors, and ependymomas) to determine their in vitro efficacy. These four OVs were screened on 14 patient-derived PBT cell cultures and the degree of oncolysis was assessed using an ATP-based assay. Subsequently, the observed viral efficacies were correlated to whole transcriptome data and Gene Ontology analysis was performed. Although no significant tumor type-specific OV efficacy was observed, the analysis revealed the intrinsic biological processes that associated with OV efficacy. The predictive power of the identified expression profiles was further validated in vitro by screening additional PBTs. In summary, our results demonstrate OV susceptibility of multiple patient-derived PBT entities and the ability to predict in vitro responses to OVs using unique expression profiles. Such profiles may hold promise for future OV preselection with effective oncolytic potency in a specific tumor, therewith potentially improving OV responses.

2024-03-01·Molecular therapy : the journal of the American Society of Gene Therapy

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

Article

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

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.

2023-06-27·Cancer research communications

Adjuvant Therapy with Oncolytic Adenovirus Delta-24-RGDOX After Intratumoral Adoptive T-cell Therapy Promotes Antigen Spread to Sustain Systemic Antitumor Immunity

Article

作者: He, Jiasen ; Jiang, Hong ; Fueyo, Juan ; Shin, Dong Ho ; Gomez-Manzano, Candelaria ; Yi, Yanhua ; Gumin, Joy ; Fan, Xuejun ; Lang, Frederick F. ; Gillard, Andrew G.

Significance::

Adjuvant therapy with oncolytic viruses promotes antigen spread to potentiate localized intratumoral adoptive T-cell therapy with limited TAA targets, leading to sustainable systemic antitumor immunity to overcome tumor relapse.

100 项与 delta-24-RGD adenovirus(Erasmus Medical Center) 相关的药物交易

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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