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

Hans Joachim Wagner, Catherine M. Bollard, Stéphane Vigouroux, M. Helen Huls, Robert Anderson, H. Grant Prentice, Malcolm Brenner, Helen Heslop, Cliona M. Rooney

Research output: Contribution to journalArticle

64 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)81-91
Number of pages11
JournalCancer Gene Therapy
Volume11
Issue number2
DOIs
StatePublished - Feb 2004

Keywords

  • Adoptive immunotherapy
  • Cytotoxic T cells
  • Epstein-Barr virus
  • Hodgkin's disease
  • Interleukin 12
  • Retroviral vector

ASJC Scopus subject areas

  • Cancer Research
  • Genetics

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