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.
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.
Wagner
Hans-Joachim
HJ
Center for Gene and Cell Therapy, Baylor College of Medicine, Houston, Texas 77030, USA.
Bollard
Catherine M
CM
Vigouroux
Stéphane
S
Huls
M Helen
MH
Anderson
Robert
R
Prentice
H Grant
HG
Brenner
Malcolm K
MK
Heslop
Helen E
HE
Rooney
Cliona M
CM
D000951:Antigens, Neoplasm / Q000276:immunology*; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D015870:Gene Expression; D005822:Genetic Vectors; D004854:Herpesvirus 4, Human / Q000276:immunology* / Q000302:isolation & purification; D006689:Hodgkin Disease / Q000276:immunology / Q000628:therapy* / Q000821:virology; D006801:Humans; D016219:Immunotherapy, Adoptive; D018664:Interleukin-12 / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology / Q000637:transplantation*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014614:Vaccines, Synthetic / Q000009:adverse effects / Q000276:immunology / Q000494:pharmacology
D000951:Antigens, Neoplasm; D016207:Cytokines; D016212:Transforming Growth Factor beta; D014614:Vaccines, Synthetic; D018664:Interleukin-12