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Journal of Virology, April 2009, p. 3450-3462, Vol. 83, No. 8
0022-538X/09/$08.00+0     doi:10.1128/JVI.02561-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Novel Immunocompetent Murine Tumor Model for Evaluation of Conditionally Replication-Competent (Oncolytic) Murine Adenoviral Vectors{triangledown}

Michael Robinson,1* Betty Li,1 Ying Ge,1 Derek Ko,1 Satya Yendluri,1 Thomas Harding,1 Melinda VanRoey,1 Katherine R. Spindler,2 and Karin Jooss1

Cell Genesys, Inc., 500 Forbes Blvd., South San Francisco, California 94080,1 Department of Microbiology & Immunology, University of Michigan Medical School, 1150 W. Medical Center Dr., 6724 Medical Science II, Ann Arbor, Michigan 48109-56202

Received 11 December 2008/ Accepted 26 January 2009

Oncolytic adenoviral vectors that express immunostimulatory transgenes are currently being evaluated in clinic. Preclinical testing of these vectors has thus far been limited to immunodeficient xenograft tumor models since human adenoviruses do not replicate effectively in murine tumor cells. The effect of the immunostimulatory transgene on overall virus potency can therefore not be readily assessed in these models. Here, a model is described that allows the effective testing of mouse armed oncolytic adenovirus (MAV) vectors in immunocompetent syngeneic tumor models. These studies demonstrate that the MAV vectors have a high level of cytotoxicity in a wide range of murine tumor cells. The murine oncolytic viruses were successfully armed with murine granulocyte-macrophage colony-stimulating factor (mGM-CSF) by a novel method which resulted in vectors with a high level of tumor-specific transgene expression. The mGM-CSF-armed MAV vectors showed an improved level of antitumor potency and induced a systemic antitumor immune response that was greater than that induced by unarmed parental vectors in immunocompetent syngeneic tumor models. Thus, the oncolytic MAV-1 system described here provides a murine homolog model for the testing of murine armed oncolytic adenovirus vectors in immunocompetent animals. The model allows evaluation of the impact of virus replication and the host immune response on overall virus potency and enables the generation of translational data that will be important for guiding the clinical development of these viruses.

* Corresponding author. Mailing address: Cell Genesys, Inc., 500 Forbes Blvd., South San Francisco, CA 94080. Phone: (415) 746-1511. Fax: (415) 512-7022. E-mail: michrobinson{at}gmail.com

{triangledown} Published ahead of print on 4 February 2009.

Journal of Virology, April 2009, p. 3450-3462, Vol. 83, No. 8
0022-538X/09/$08.00+0     doi:10.1128/JVI.02561-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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