Safety and efficacy of VCN-01, an oncolytic adenovirus combining fiber HSG-binding domain replacement with RGD and hyaluronidase expression.
OBJECTIVE
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.


METHODS
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.
Translational Research Laboratory, IDIBELL-Institut Català d'Oncologia, L'Hospitalet de Llobregat, Barcelona, Spain.
Alba
A
Rodríguez-García
VCN Biosciences, Sant Cugat del Vallès, Barcelona, Spain.
Marta
M
Giménez-Alejandre
Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
Juan J
JJ
Rojas
Translational Research Laboratory, IDIBELL-Institut Català d'Oncologia, L'Hospitalet de Llobregat, Barcelona, Spain.
Rafael
R
Moreno
VCN Biosciences, Sant Cugat del Vallès, Barcelona, Spain.
Miriam
M
Bazan-Peregrino
VCN Biosciences, Sant Cugat del Vallès, Barcelona, Spain.
Manel
M
Cascalló
Translational Research Laboratory, IDIBELL-Institut Català d'Oncologia, L'Hospitalet de Llobregat, Barcelona, Spain. ralemany@iconcologia.net.
Ramon
R
Alemany
D000230:Adenocarcinoma / Q000628:therapy*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D006224:Cricetinae; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006821:Hyaluronoglucosaminidase / Q000096:biosynthesis / Q000235:genetics; D007515:Islets of Langerhans / Q000821:virology; D008297:Male; D008545:Melanoma / Q000628:therapy*; D008647:Mesocricetus; D051379:Mice; D008807:Mice, Inbred BALB C; D050130:Oncolytic Virotherapy / Q000009:adverse effects / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000628:therapy*; D011485:Protein Binding; D023041:Xenograft Model Antitumor Assays
D002352:Carrier Proteins; D019812:Heparan Sulfate Proteoglycans; D006821:Hyaluronoglucosaminidase