Hyaluronidase Expression by an Oncolytic Adenovirus Enhances Its Intratumoral Spread and Suppresses Tumor Growth

Guedan, Sonia; Rojas, Juan J.; Gros, Alena; Mercadé, Montse; Cascalló, Manel; Alemany, Ramón

doi:10.1038/mt.2010.79

Cited by 184 publications

(166 citation statements)

References 28 publications

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“…The PCR product, containing the GALV cassette, was digested with EcoR I and ligated to the pNKFiberRGD plasmid 19 to generate pNKFiberGALV. The Not I-Kpn I fragment of pNKFiberGALV and the partially Swa I digested pVK50cau 12 were recombined by homologous recombination, performed in yeast. This recombination event resulted in generation of the pAdwtRGD --GALV.…”

Section: Methodsmentioning

confidence: 99%

GALV expression enhances the therapeutic efficacy of an oncolytic adenovirus by inducing cell fusion and enhancing virus distribution

et al. 2011

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The limitations of the current oncolytic adenoviruses for cancer therapy include insufficient potency and poor distribution of the virus throughout the tumor mass. To address these problems, we generated an oncolytic adenovirus expressing the hyperfusogenic form of the gibbon-ape leukemia virus (GALV) envelope glycoprotein under the control of the adenovirus major late promoter. The oncolytic properties of the new fusogenic adenovirus, ICOVIR16, were analyzed both in vitro and in vivo, and compared with that of its non-fusogenic counterpart, ICOVIR15. Our results indicate that GALV expression by ICOVIR16 induced extensive syncytia formation and enhanced tumor cell killing in a variety of tumor cell types. When injected intratumorally or intravenously into mice with large pre-established melanoma or pancreatic tumors, ICOVIR16 rapidly reduced tumor burden, and in some cases, resulted in complete eradication of the tumors. Importantly, GALV expression induced tumor cell fusion in vivo and enhanced the spreading of the virus throughout the tumor. Taken together, these results indicate that GALV expression can improve the antitumoral potency of an oncolytic adenovirus and suggest that ICOVIR16 is a promising candidate for clinical evaluation in patients with cancer.

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Section: Methodsmentioning

confidence: 99%

GALV expression enhances the therapeutic efficacy of an oncolytic adenovirus by inducing cell fusion and enhancing virus distribution

et al. 2011

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“…Adwt-RGDK was created by replacing the wild-type fiber for the RGDK fiber in the adenovirus 5 wild-type genome. To achieve this, an EcoRI digestion fragment of the pBSattKKT plasmid 15 containing the RGK fiber was recombined in Saccharomyces cerevisiae YPH857 with the pVK50-CAU plasmid 21 linearized with SwaI to create pAdwt-RGDK-CAU. Adwt-RGDK was obtained by transfection into HEK293 cells of the large PacI fragment of pAdwt-RGDK-CAU.…”

Section: Virusesmentioning

confidence: 99%

Improved systemic antitumor therapy with oncolytic adenoviruses by replacing the fiber shaft HSG-binding domain with RGD

et al. 2011

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Retargeting oncolytic adenoviruses from their systemic preeminent liver tropism to disseminated tumor foci would highly improve the efficacy of these agents at eradicating tumors. We have replaced the KKTK fiber shaft heparan sulfate glycosaminoglycan-binding domain with an RGDK motif in order to achieve simultaneously liver detargeting and tumor targeting. When inserted into a wild-type backbone, this mutation palliated liver transaminase elevation and hematological alterations in mice. Importantly, when tested in a backbone that redirects E1A transcription towards pRB pathway deregulation, RGD at this novel shaft location also improved significantly systemic antitumor therapy compared with the broadly used RGD location at the HI-loop of the fiber knob domain. Gene Therapy (2012) Keywords: oncolytic adenovirus; fiber shaft; HSG-binding domain; RGD motif; antitumor efficacy INTRODUCTION Oncolytic adenoviruses are promising therapies for cancer treatment owing to their ability to self-amplify at the tumor site. However, systemic delivery of Ad5 results in a rapid clearance from the bloodstream and the sequestration of the virus in the liver, which causes toxicity and a drop in virus bioavailability. 1 As the success of adenoviral therapy depends on the ability of adenoviruses to reach disseminated cancer cells, this liver tropism limits the efficacy of the therapy upon systemic administration. To overcome this limitation, capsid retargeting mutations are under study.To retarget Ad5 to tumor sites, it is necessary to abrogate liver transduction (liver detargeting) and to expose new ligands specific for tumor cells on capsid proteins (tumor targeting). To achieve liver detargeting, several mutations on capsid proteins, such as the double ablation of CAR and integrin binding, have failed to reduce hepatocyte transduction in vivo owing to the role of blood factors in adenovirus liver transduction. 2,3 Recently, ablation of Factor X binding by the hexon has resulted in successful liver-detargeting, 4,5 although this might be at the expense of lower tumor targeting. 6 Alternatively, the mutation of the heparan sulfate glycosaminoglycan (HSG) putative-binding site KKTK of the Ad5 fiber shaft domain detargets liver transduction, probably because of affectation of the bending or structure of the fiber. 2,7,8 On the other hand, the HI-loop of the fiber knob domain has been used to accommodate a broad range of tumor-selective peptides for tumor targeting 9-11 Among all peptides incorporated into the HI loop, the CDCRGDCFC motif (known as RGD-4C) has been broadly used and confers on Ad5 a CAR-independent entry mechanism by using aV-b3 and aV-b5 integrins as primary receptors. 12,13 As integrins are a large family of adhesive receptors involved in the spread and adhesion

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“…To tackle this problem, oncolytic viruses have been armed with ECM-degrading enzymes such as relaxin, decorin, metalloprotease-9, chondroitinase ABC (16)(17)(18)(19)(20), or PH20 hyaluronidase as we have previously reported (21). In addition, recombinant hyaluronidase enhances the penetration and efficacy of several chemotherapeutic agents including docetaxel, doxorubicin, or gemcitabine, presumably due to a reduction of the IFP in tumors (22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

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

Rodríguez-García

Giménez-Alejandre

Rojas

et al. 2015

Clinical Cancer Research

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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.

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Hyaluronidase Expression by an Oncolytic Adenovirus Enhances Its Intratumoral Spread and Suppresses Tumor Growth

Cited by 184 publications

References 28 publications

GALV expression enhances the therapeutic efficacy of an oncolytic adenovirus by inducing cell fusion and enhancing virus distribution

GALV expression enhances the therapeutic efficacy of an oncolytic adenovirus by inducing cell fusion and enhancing virus distribution

Improved systemic antitumor therapy with oncolytic adenoviruses by replacing the fiber shaft HSG-binding domain with RGD

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

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