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
| Autor: | Cliona M. Rooney, M. Helen Huls, Malcolm K. Brenner, Robert H. Anderson, H. Grant Prentice, Catherine M. Bollard, Stephane Vigouroux, Helen E. Heslop, Hans-Joachim Wagner |
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| Rok vydání: | 2003 |
| Předmět: |
Herpesvirus 4
Human Cancer Research CD30 medicine.medical_treatment Genetic Vectors Gene Expression Biology Immunotherapy Adoptive Cell Line Antigens Neoplasm Transforming Growth Factor beta medicine Humans Cytotoxic T cell Interferon gamma Molecular Biology Interleukin 4 Vaccines Synthetic hemic and immune systems Immunotherapy Hodgkin Disease Interleukin-12 Tumor antigen CTL Retroviridae Immunology Interleukin 12 Cytokines Molecular Medicine T-Lymphocytes Cytotoxic medicine.drug |
| Zdroj: | Cancer Gene Therapy. 11:81-91 |
| ISSN: | 1476-5500 0929-1903 |
| DOI: | 10.1038/sj.cgt.7700664 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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