Abstract
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. 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. 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. 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.
Highlights
The use of viruses to treat cancer is an old concept that has been revisited during the last two decades with viruses genetically modified to acquire selectivity and potency
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
As VCN-01, they are based in ICOVIR-15, a virus with E1a mutated in the pRBbinding site and under the control of minimal E2F binding sites to allow for selective replication in a broad range of tumor cells with pRB pathway alterations [31]
Summary
The use of viruses to treat cancer is an old concept that has been revisited during the last two decades with viruses genetically modified to acquire selectivity and potency. Genetically modified herpes simplex virus, vaccinia viruses, and adenoviruses are in phase III clinical trials. GM-CSF expression by these viruses seeks to elicit antitumor immunotherapy [1, 2]. Despite that this immune mechanism of action is expected to be systemic, the strong local immunosuppressive tumor environment may require that the virus reaches and replicates in all tumor nodules for effectiveness [3]. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/)
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