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

Successful virotherapy requires efficient virus spread within tumors. We tested whether the expression of hyaluronidase, an enzyme which dissociates the extracellular matrix (ECM), could enhance the intratumoral distribution of an oncolytic adenovirus and improve its therapeutic activity. As a proof...

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Bibliographic Details
Published in:Molecular therapy 2010-07, Vol.18 (7), p.1275-1283
Main Authors: Guedan, Sonia, Rojas, Juan José, Gros, Alena, Mercade, Elena, Cascallo, Manel, Alemany, Ramon
Format: Article
Language:English
Subjects:
Adenoviridae - genetics
Adenoviridae - physiology
Adenoviruses
Animals
Binding sites
Cancer
Cattle
Cell Line
Cell Line, Tumor
Cricetinae
Female
Gene Expression Regulation, Enzymologic
Humans
Hyaluronic acid
Hyaluronoglucosaminidase - genetics
Hyaluronoglucosaminidase - metabolism
Immunohistochemistry
Male
Melanoma
Melanoma - therapy
Mesocricetus
Mice
Mice, Inbred BALB C
Oncolytic Virotherapy
Original
Peptides
Sperm
Tumors
Viruses
Xenograft Model Antitumor Assays
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Summary:Successful virotherapy requires efficient virus spread within tumors. We tested whether the expression of hyaluronidase, an enzyme which dissociates the extracellular matrix (ECM), could enhance the intratumoral distribution of an oncolytic adenovirus and improve its therapeutic activity. As a proof of concept, we demonstrated that intratumoral coadministration of hyaluronidase in mice-bearing tumor xenografts improves the antitumor activity of an oncolytic adenovirus. Next, we constructed a replication-competent adenovirus expressing a soluble form of the human sperm hyaluronidase (PH20) under the control of the major late promoter (MLP) (AdwtRGD-PH20). Intratumoral treatment of human melanoma xenografts with AdwtRGD-PH20 resulted in degradation of hyaluronan (HA), enhanced viral distribution, and induced tumor regression in all treated tumors. Finally, the PH20 cDNA was inserted in an oncolytic adenovirus that selectively kills pRb pathway-defective tumor cells. The antitumoral activity of the novel oncolytic adenovirus expressing PH20 (ICOVIR17) was compared to that of the parental virus ICOVIR15. ICOVIR17 showed more antitumor efficacy following intratumoral and systemic administration in mice with prestablished tumors, along with an improved spread of the virus within the tumor. Importantly, a single intravenous dose of ICOVIR17 induced tumor regression in 60% of treated tumors. These results indicate that ICOVIR17 is a promising candidate for clinical testing.
ISSN:1525-0016
1525-0024
DOI:10.1038/mt.2010.79