Martinez-Velez N.,University of Navarra |
Martinez-Velez N.,Foundation for the Applied Medical Research |
Xipell E.,University of Navarra |
Xipell E.,Foundation for the Applied Medical Research |
And 14 more authors.
Clinical Cancer Research | Year: 2016
Purpose: Osteosarcoma is the most common malignant bone tumor in children and adolescents. Despite aggressive chemotherapy, more than 30% of patients do not respond and develop bone or lung metastasis. Oncolytic adenoviruses engineered to specifically destroy cancer cells are a feasible option for osteosarcoma treatment. VCN-01 is a replication-competent adenovirus specifically engineered to replicate in tumors with a defective RB pathway, presents an enhanced infectivity through a modified fiber and an improved distribution through the expression of a soluble hyaluronidase. The aim of this study is to elucidate whether the use of VCN-01 would be an effective therapeutic strategy for pediatric osteosarcoma. Experimental Design: We used osteosarcoma cell lines established from patients with metastatic disease (531MII, 678R, 588M, and 595M) and a commercial cell line (143B). MTT assays were carried out to evaluate the cytotoxicity of VCN-01. Hexon assays were used to evaluate the replication of the virus. Western blot analysis was performed to assess the expression levels of viral proteins and autophagic markers. The antitumor effect of VCN-01 was evaluated in orthotopic and metastatic osteosarcoma murine animal models. Results: This study found that VCN-01, a new generation genetically modified oncolytic adenovirus, administered locally or systemically, had a potent antisarcoma effect in vitro and in vivo in mouse models of intratibial and lung metastatic osteosarcoma. Moreover, VCN-01 administration showed a safe toxicity profile. Conclusions: These results uncover VCN-01 as a promising strategy for osteosarcoma, setting the bases to propel a phase I/II trial for kids with this disease. © 2016 American Association for Cancer Research. Source
Laborda E.,IDIBELL Institute Catala dOncologia |
Laborda E.,Autonomous University of Barcelona |
Puig-Saus C.,IDIBELL Institute Catala dOncologia |
Cascallo M.,VCN Biosciences |
And 3 more authors.
Human Gene Therapy Methods | Year: 2013
The contamination of adenovirus (Ad) stocks with adeno-associated viruses (AAV) is usually unnoticed, and it has been associated with lower Ad yields upon large-scale production. During Ad propagation, AAV contamination needs to be detected routinely by polymerase chain reaction without symptomatic suspicion. In this study, we describe that the coinfection of either Ad wild type 5 or oncolytic Ad with AAV results in a large-plaque phenotype associated with an accelerated release of Ad from coinfected cells. This accelerated release was accompanied with the expected decrease in Ad yields in two out of three cell lines tested. Despite this lower Ad yield, coinfection with AAV accelerated cell death and enhanced the cytotoxicity mediated by Ad propagation. Intratumoral coinjection of Ad and AAV in two xenograft tumor models improved antitumor activity and mouse survival. Therefore, we conclude that accidental or intentional AAV coinfection has important implications for Ad-mediated virotherapy. © Mary Ann Liebert, Inc. Source
Rodriguez-Garcia A.,IDIBELL Institute Catala dOncologia |
Gimenez-Alejandre M.,VCN Biosciences |
Rojas J.J.,University of Pittsburgh |
Moreno R.,IDIBELL Institute Catala dOncologia |
And 3 more authors.
Clinical Cancer Research | Year: 2015
Purpose: Tumor targeting upon intravenous administration and subsequent intratumoral virus dissemination are key features to improve oncolytic adenovirus therapy. VCN-01 is a novel oncolytic adenovirus that combines selective replication conditional to pRB pathway deregulation, replacement of the heparan sulfate glycosaminoglycan putative-binding site KKTK of the fiber shaft with an integrin-binding motif RGDK for tumor targeting, and expression of hyaluronidase to degrade the extracellular matrix. In this study, we evaluate the safety and efficacy profile of this novel oncolytic adenovirus. Experimental Design: VCN-01 replication and potency were assessed in a panel of tumor cell lines. VCN-01 tumor-selective replication was evaluated in human fibroblasts and pancreatic islets. Preclinical toxicity, biodistribution, and efficacy studies were conducted in mice and Syrian hamsters. Results: Toxicity and biodistribution preclinical studies support the selectivity and safety of VCN-01. Antitumor activity after intravenous or intratumoral administration of the virus was observed in all tumor models tested, including melanoma and pancreatic adenocarcinoma, both in immunodeficient mice and immunocompetent hamsters. Conclusions: Oncolytic adenovirus VCN-01 characterized by the expression of hyaluronidase and the RGD shaft retargeting ligand shows an efficacy- toxicity prolife in mice and hamsters by intravenous and intratumoral administration that warrants clinical testing. ©2014 AACR. Source
Laborda E.,Institute Catala dOncologia |
Laborda E.,Autonomous University of Barcelona |
Puig-Saus C.,Institute Catala dOncologia |
Rodriguez-Garcia A.,Institute Catala dOncologia |
And 4 more authors.
Molecular Therapy | Year: 2014
Human and canine cancer share similarities such as genetic and molecular aspects, biological complexity, tumor epidemiology, and targeted therapeutic treatment. Lack of good animal models for human adenovirotherapy has spurred the use of canine adenovirus 2-based oncolytic viruses. We have constructed a canine oncolytic virus that mimics the characteristics of our previously published human adenovirus ICOVIR17: expression of E1a controlled by E2F sites, deletion of the pRb-binding site of E1a, insertion of an RGD integrin-binding motif at the fiber Knob, and expression of hyaluronidase under the major late promoter/IIIa protein splicing acceptor control. Preclinical studies showed selectivity, increased cytotoxicity, and strong hyaluronidase activity. Intratumoral treatment of canine osteosarcoma and melanoma xenografts in mice resulted in inhibition of tumor growth and prolonged survival. Moreover, we treated six dogs with different tumor types, including one adenoma, two osteosarcomas, one mastocitoma, one fibrosarcoma, and one neuroendocrine hepatic carcinoma. No virus-associated adverse effects were observed, but toxicity associated to tumor lysis, including disseminated intravascular coagulation and systemic failure, was found in one case. Two partial responses and two stable diseases warrant additional clinical testing. © 2014 The American Society of Gene and Cell Therapy. Source