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A strategy for treatment of Epstein–Barr virus-positive Hodgkin's disease by targeting interleukin 12 to the tumor environment using tumor antigen-specific T cells

Cancer Gene Therapy volume 11, pages 81–91 (2004)Cite this article

Abstract

Adoptive immunotherapy with Epstein–Barr virus (EBV)-specific cytotoxic T cells (CTL) is effective for the prophylaxis and treatment of EBV-induced lymphoma in hematopoietic stem cell recipients. However, in EBV-positive Hodgkin's disease (HD) the efficacy of adoptively transferred EBV-specific CTL may be limited by tumor-derived immunosuppressive factors, such as T-cell growth factor (TGF) β, interleukin (IL)13 and the chemokine TARC. Local delivery of IL12 to tumor sites by tumor-specific CTL could provide direct antitumor effects and overcome the CTL-inhibitory effects of the Th2 tumor environment while avoiding the systemic toxicity of recombinant IL12. EBV-specific CTL transduced with a retrovirus vector expressing the p40 and p35 subunits of IL12 as a single molecule (Flexi-IL12), produced IL12 following antigenic stimulation. This resulted in an elevated production of Th1 cytokines, including interferon γ and tumor necrosis factor α, and a reduction in the Th2 cytokines IL4 and IL5. Flexi-IL12-transduced CTL resisted the antiproliferative and anticytotoxic effects of exogenous TGFβ, likely by antagonizing the TGFβ-induced downregulation of the Th1 transcriptional factor T-bet. In addition, Flexi-IL12-transduced CTL demonstrated a proliferative advantage in the presence of inhibitory supernatants from HD-derived cell lines. Tumor-specific, Flexi-IL12-transduced EBV-specific CTL should have a functional advantage over unmodified CTL, particularly in the presence of the adverse Th2 cytokine environment produced by Hodgkin tumor cells.

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Acknowledgements

This work was supported by a grant from the “Deutsche Forschungsgemeinschaft” to HJW (WA 1149/2-1), a grant from the “Association pour la Recherche sur le Cancer (ARC), France” to SV, a Translational Research Grant (# 6104-02) from the Leukemia and Lymphoma Society of America to CMR, POI CA94237 from the National Institutes of Health, a Distinguished Clinical Scientist Award from the Doris Duke Foundation to HEH and by the Center for Cell and Gene Therapy, Baylor College of Medicine.

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Authors and Affiliations

  1. Center for Gene and Cell Therapy, Baylor College of Medicine, Houston, 77030, Texas, USA

    Hans-Joachim Wagner, Catherine M Bollard, Stéphane Vigouroux, M Helen Huls, Malcolm K Brenner, Helen E Heslop & Cliona M Rooney

  2. Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA

    Hans-Joachim Wagner, Catherine M Bollard, Stéphane Vigouroux & M Helen Huls

  3. Department of Medicine, Baylor College of Medicine, Houston, Texas, USA

    Malcolm K Brenner & Helen E Heslop

  4. Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA

    Cliona M Rooney

  5. Department of Hematology, Royal Free Campus, London, UK

    Robert Anderson & H Grant Prentice

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  1. Hans-Joachim Wagner
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Correspondence to Cliona M Rooney.

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Wagner, HJ., Bollard, C., Vigouroux, S. et al. A strategy for treatment of Epstein–Barr virus-positive Hodgkin's disease by targeting interleukin 12 to the tumor environment using tumor antigen-specific T cells. Cancer Gene Ther 11, 81–91 (2004). https://doi.org/10.1038/sj.cgt.7700664

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