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Journal of Virology, May 2005, p. 5455-5465, Vol. 79, No. 9
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.9.5455-5465.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Linked Tumor-Selective Virus Replication and Transgene Expression from E3-Containing Oncolytic Adenoviruses{dagger}

Mingzhu Zhu, J. Andrew Bristol, Yuefeng Xie, Mervat Mina, Hong Ji, Suzanne Forry-Schaudies, and David L. Ennist*

Immunology Program, Oncology Unit, Genetic Therapy, Inc., Bethesda, Maryland

Received 25 August 2004/ Accepted 19 November 2004

Historically, the adenoviral E3 region was found to be nonessential for viral replication in vitro. In addition, adenoviruses whose genome was more than approximately 105% the size of the native genome were inefficiently packaged. These profound observations were used experimentally to insert transgenes into the adenoviral backbone. More recently, however, the reintroduction of the E3 region into oncolytic adenoviruses has been found to positively influence antitumor efficacy in preclinical models and clinical trials. In the studies reported here, the granulocyte-macrophage colony-stimulating factor (GM-CSF) cDNA sequence has been substituted for the E3-gp19 gene in oncolytic adenoviruses that otherwise retained the E3 region. Five viruses that differed slightly in the method of transgene insertion were generated and compared to Ar6pAE2fGmF (E2F/GM/{Delta}E3), a previously described E3-deleted oncolytic adenovirus encoding GM-CSF. In all of the viruses, the human E2F-1 promoter regulated E1A expression and GM-CSF expression was under the control of the adenoviral E3 promoter and the packaging signal was relocated immediately upstream from the right terminal repeat. The E3-gp19-deleted viruses had similar cytolytic properties, as measured in vitro by cytotoxicity assays, but differed markedly in their capacity to express and secrete GM-CSF. Ar15pAE2fGmF (E2F/GM/E3b), the virus that produced the highest levels of GM-CSF and retained the native GM-CSF leader sequence, was selected for further analysis. The E2F/GM/E3b and E2F/GM/{Delta}E3 viruses exhibited similar cytotoxic activity and GM-CSF production in several tumor cell lines in vitro. However, when compared in vivo in nude mouse xenograft tumor models, E2F/GM/E3b spread through tumors to a greater extent, resulted in higher peak GM-CSF and total exposure levels in both tumor and serum, and was more efficacious than the E3-deleted virus. Using the matched WI-38 (parental) and WI-38-VA13 (simian virus 40 large T antigen transformed) cell pair, GM-CSF was shown to be selectively produced in cells expressing high levels of E2F, indicating that the tumor-selective E2F promoter controlled E1A and GM-CSF expression.

* Corresponding author. Mailing address: 9715 De Paul Drive, Bethesda, MD 20817. Phone: (301) 466-7693. Fax: (301) 530-6224. E-mail: dle1{at}comcast.net.

{dagger} Reprint requests should be addressed to Susan Bryan, Cell Genesys, Inc., 500 Forbes Avenue, South San Francisco, CA 94080, Susan.Bryan@cellgenesys.com.

Journal of Virology, May 2005, p. 5455-5465, Vol. 79, No. 9
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.9.5455-5465.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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