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. 2004 Feb;11(2):81-91. doi: 10.1038/sj.cgt.7700664.


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) beta, 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 gamma and tumor necrosis factor alpha, and a reduction in the Th2 cytokines IL4 and IL5. Flexi-IL12-transduced CTL resisted the antiproliferative and anticytotoxic effects of exogenous TGFbeta, likely by antagonizing the TGFbeta-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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antigens, Neoplasm / immunology*
  • Cell Line
  • Cytokines / biosynthesis
  • Gene Expression
  • Genetic Vectors
  • Herpesvirus 4, Human / immunology*
  • Herpesvirus 4, Human / isolation & purification
  • Hodgkin Disease / immunology
  • Hodgkin Disease / therapy*
  • Hodgkin Disease / virology
  • Humans
  • Immunotherapy, Adoptive*
  • Interleukin-12 / genetics*
  • Retroviridae / genetics
  • Retroviridae / immunology
  • T-Lymphocytes, Cytotoxic / cytology
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / transplantation*
  • Transforming Growth Factor beta / pharmacology
  • Vaccines, Synthetic / adverse effects
  • Vaccines, Synthetic / immunology
  • Vaccines, Synthetic / pharmacology


  • Antigens, Neoplasm
  • Cytokines
  • Transforming Growth Factor beta
  • Vaccines, Synthetic
  • Interleukin-12