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Gene therapy of ovarian cancer with IFN-α-producing fibroblasts: comparison of constitutive and inducible vectors

Gene Therapy volume 13, pages 953–965 (2006)Cite this article

Abstract

Ovarian cancer represents a malignancy suitable for cell and gene therapy approaches owing to its containment within the peritoneal cavity, even at advanced tumor stages. As regulation of transgene expression would be preferable for conducting clinical trials for reasons of safety, we investigated whether intraperitoneal (i.p.) administration of retroviral vector-transduced fibroblasts encoding murine interferon-α (IFN-α) could have therapeutic activity, and compared its effect with the antitumor effects of fibroblasts producing IFN-α under a rapamycin analogue (AP21967)-inducible promoter. Human and murine fibroblasts were recruited into the solid component of transplantable ovarian cancer-grown i.p. in severe combined immunodeficiency mice. Multiple administrations of fibroblasts producing IFN-α in a constitutive manner showed therapeutic efficacy, leading to significant prolongation of survival in the majority of animals, associated with inhibition of tumor angiogenesis. Compared to cells transduced by the constitutive vector, fibroblasts transduced by the inducible vector released twofold higher IFN-α levels in vitro, following induction by AP21967, and production of the cytokine was under pharmacologic control both in vitro and in vivo. However, these cells elicited only modest therapeutic effects in vivo. Overall, these findings indicate that intracavitary IFN-α gene therapy using engineered fibroblasts requires sustained production of IFN-α to achieve durable antitumor effects.

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Acknowledgements

We thank Mrs A Azzalini and P Gallo for artwork and Dr Erich Piovan for help in preparing the manuscript. We thank ARIAD Pharmaceuticals Inc. (Cambridge, MA, USA) for providing us with the Argent Regulated Transcription Retrovirus Kit and with AP21967. This work was supported in part by grants from MIUR 40 and 60%, FIRB, the Italian Association for Cancer Research (AIRC), the Ministero della Salute (Ricerca Finalizzata 2002), the Italian Foundation for Cancer Research (FIRC), and the Fondazione Cassa di Risparmio di Padova e Rovigo.

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Author notes

  1. S Indraccolo and L Moserle: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology and Surgical Sciences, University of Padova, Padova, Italy

    S Indraccolo, L Moserle, V Tisato, E Gola, S Minuzzo, L Persano, L Chieco-Bianchi & A Amadori

  2. Azienda Ospedaliera, Padova, Italy

    S Indraccolo & A Amadori

  3. Istituto Oncologico Veneto, Padova, Italy

    S Indraccolo, L Chieco-Bianchi & A Amadori

  4. University of Tübingen, Germany

    V Roni

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  1. S Indraccolo
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Correspondence to S Indraccolo.

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Indraccolo, S., Moserle, L., Tisato, V. et al. Gene therapy of ovarian cancer with IFN-α-producing fibroblasts: comparison of constitutive and inducible vectors. Gene Ther 13, 953–965 (2006). https://doi.org/10.1038/sj.gt.3302745

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