Safety and Efficacy of VCN-01, an Oncolytic Adenovirus Combining Fiber HSG-Binding Domain Replacement with RGD and Hyaluronidase Expression

Abstract

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.

The Oncolytic Adenovirus VCN-01 as Therapeutic Approach Against Pediatric Osteosarcoma

“…Virtually, the entire human population has IgG antibodies to adenovirus serotype 5, and 55% of these antibodies effectively neutralize adenoviruses (37). The insertion of an RGDK sequence into the fiber protein produced by VCN-01 considerably improved its biodistribution after systemic administration and enhanced the therapeutic effect of VCN-01 in vivo in two immunocompetent models (11,38). Currently, there are two clinical trials underway to evaluate the therapeutic effect of systemically administered VCN-01; one of these concerns VCN-01 alone and the other VCN-01 in combination with gentamicin (NTC02045602 and NTC02045589).…”

“…VCN-01 is an oncolytic adenovirus that harbors a 24-base pair deletion in the E1A region, and the native E1A promoter has been modified by the insertion of eight E2F-binding sites organized in four palindromes and one Sp1-binding site. These modifications selectively restrict the replication of VCN-01 to cells with a defective pRB pathway (11,12). In addition, the VCN-01 adenovirus displays improved infectivity and bioavailability as a result of the inclusion of an RGDK motif in the heparin sulphateglycosaminoglycans (HSG)-binding domain KKTK of the fiber shaft (13); this modification improves antitumor potency compared with the adenovirus modified with an RGD motif in the fiber HI loop (14).…”

Development of oncolytic virotherapy: from genetic modification to combination therapy

“…For example, GLV-1h255, an oncolytic VACV, can express MMP-9 to promote collagen IV degradation [152] and increase the intratumoral spread and antitumor efficacy of OV. VCN-01 is an OAd expressing PH20 hyaluronidase [155], PH20 hyaluronidase can promote the spread of OVs between tumor cells by degrading the ECM. VCN-01 has now entered clinical trials for the treatment of pancreatic adenocarcinoma and retinoblastoma [156].…”

Oncolytic viral therapy for pancreatic cancer

“…VCN‐01, another oncolytic adenovirus engineered to replicate only in cells with a disrupted Rb pathway, carries a gene encoding PH20 hyaluronidase, a stromal agent similar to PEGPH20 (intravenous hyaluronidase). VCN‐01 therefore targets both PDA cells for lysis but also degrades extracellular matrix of the dense surrounding stroma, thus potentiating its own access to tumor cells.…”