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E1A-expressing adenoviral E3B mutants act synergistically with chemotherapeutics in immunocompetent tumor models

Cancer Gene Therapy volume 15, pages 40–50 (2008)Cite this article

Abstract

The majority of clinical trials evaluating replication-selective oncolytic adenoviruses utilized mutants with immunomodulatory E3B genes deleted, likely contributing to the attenuated efficacy. We investigated whether an intact immune response could contribute to the observed improved efficacy in response to combinations with chemotherapeutics. Seven carcinoma cell lines were evaluated by combining viral mutants; dl309 (ΔE3B), dl704 (ΔE3gp19K), dl312 (ΔE1A) or wild-type Ad5 with the commonly used clinical drugs cisplatin and paclitaxel. Synergistic effects on cell death were determined by generation of combination indexes in cultured cells. In vivo tumor growth inhibition was achieved by virotherapy alone and was most efficacious with wild-type virus and least with the ΔE3B mutant. Significantly higher efficacy was observed when the viruses were combined with drugs. The greatest enhancement of tumor inhibition was in combination with the ΔE3B mutant restoring potency to that of Ad5 wild-type levels, observed only in animals with intact immune response. Increases in infectivity, viral gene expression and replication were identified as potential mechanisms contributing to the synergistic effects. Our results suggest that the attenuation of ΔE3B mutants can be overcome by low doses of chemotherapeutics only in the presence of an intact immune response indicating a role for T-cell-mediated functions.

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Acknowledgements

We want to thank Gary Martin (CRUK, London, UK) and colleagues at Clare Hall for excellent experimental assistance and Jennelle Francis (Molecular Oncology Unit) for production and characterization of all viral mutants. We also wish to thank Lynda Hawkins, Patricia Ryan and Jingping Yang (GTI-Novartis, Gaithersburg, MD) for helpful and insightful discussions.

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Authors and Affiliations

  1. Centre for Molecular Oncology, Institute of Cancer, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

    S C Cheong, Y Wang, J-H Meng, R Hill, K Sweeney, N R Lemoine & G Halldén

  2. Department of Pharmacology, Oxford University Medical School, Oxford, UK

    D Kirn

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  1. S C Cheong
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Correspondence to G Halldén.

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Supplementary Information accompanies the paper on Cancer Gene Therapy website (http://www.nature.com/cgt)

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Cheong, S., Wang, Y., Meng, JH. et al. E1A-expressing adenoviral E3B mutants act synergistically with chemotherapeutics in immunocompetent tumor models. Cancer Gene Ther 15, 40–50 (2008). https://doi.org/10.1038/sj.cgt.7701099

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