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Targeted cancer immunotherapy with oncolytic adenovirus coding for a fully human monoclonal antibody specific for CTLA-4

Gene Therapy volume 19, pages 988–998 (2012)Cite this article

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Abstract

Promising clinical results have been achieved with monoclonal antibodies (mAbs) such as ipilimumab and tremelimumab that block cytotoxic T lymphocyte-associated antigen-4 (CTLA-4, CD152). However, systemic administration of these agents also has the potential for severe immune-related adverse events. Thus, local production might allow higher concentrations at the target while reducing systemic side effects. We generated a transductionally and transcriptionally targeted oncolytic adenovirus Ad5/3-Δ24aCTLA4 expressing complete human mAb specific for CTLA-4 and tested it in vitro, in vivo and in peripheral blood mononuclear cells (PBMCs) of normal donors and patients with advanced solid tumors. mAb expression was confirmed by western blotting and immunohistochemistry. Biological functionality was determined in a T-cell line and in PBMCs from cancer patients. T cells of patients, but not those of healthy donors, were activated by an anti-CTLA4mAb produced by Ad5/3-Δ24aCTLA4. In addition to immunological effects, a direct anti-CTLA-4-mediated pro-apoptotic effect was observed in vitro and in vivo. Local production resulted in 43-fold higher (P<0.05) tumor versus plasma anti-CTLA4mAb concentration. Plasma levels in mice remained below what has been reported safe in humans. Replication-competent Ad5/3-Δ24aCTLA4 resulted in 81-fold higher (P<0.05) tumor mAb levels as compared with a replication-deficient control. This is the first report of an oncolytic adenovirus producing a full-length human mAb. High mAb concentrations were seen at tumors with lower systemic levels. Stimulation of T cells of cancer patients by Ad5/3-Δ24aCTLA4 suggests feasibility of testing the approach in clinical trials.

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Acknowledgements

We thank Päivi Hannuksela, Sirkka-Liisa Holm, Eerika Karli and Aila Karioja-Kallio for technical assistance. Financial support: Financial support was received from Helsinki Biomedical Graduate School, European Research Council, Helsinki University Central Hospital, Sigrid Juselius Foundation, Academy of Finland, Emil Aaltonen Foundation, ASCO Foundation, Biocenter Finland, the Biomedicum Foundation, Finnish Cancer Society, Biocentrum Helsinki, the K Albin Johansson Foundation, University of Helsinki and the Finnish Cultural Foundation. Akseli Hemminki is K Albin Johansson Research Professor of the Foundation for the Finnish Cancer Institute.

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  1. J D Dias and O Hemminki: These authors equally contributed to this work.

Authors and Affiliations

  1. Cancer Gene Therapy Group, Molecular Cancer Biology Program & Transplantation Laboratory & Haartman Institute, & Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland

    J D Dias, O Hemminki, I Diaconu, M Hirvinen, K Guse, S Escutenaire, A Kanerva, S Pesonen, V Cerullo & A Hemminki

  2. HUSLAB, Helsinki University Central Hospital, Helsinki, Finland

    J D Dias, O Hemminki, I Diaconu, M Hirvinen, K Guse, S Escutenaire, S Pesonen, V Cerullo & A Hemminki

  3. Molecular Neurology Research Program, University of Helsinki, Helsinki, Finland

    A Bonetti

  4. Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland

    A Kanerva

  5. Department of Immunology, Genetics and Pathology, Uppsala University, Helsinki, Sweden

    A Löskog

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  1. J D Dias
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Correspondence to V Cerullo or A Hemminki.

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Akseli Hemminki is cofounder and shareholder in Oncos Therapeutics Ltd.

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Dias, J., Hemminki, O., Diaconu, I. et al. Targeted cancer immunotherapy with oncolytic adenovirus coding for a fully human monoclonal antibody specific for CTLA-4. Gene Ther 19, 988–998 (2012). https://doi.org/10.1038/gt.2011.176

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