Lentiviral vector expression of tumour antigens in dendritic cells as an immunotherapeutic strategy.
Therapeutic cancer vaccines need to stimulate a refractory immune system to make an effective anti-tumour response. We have explored the use of lentiviral vectors to deliver tumour antigen genes to dendritic cells (DC) as a possible mechanism of immune stimulation. Direct injection of a lentiviral vector encoding the melanoma antigen NY-ESO-1 in HLA-A2 transgenic mice primed NY-ESO-1-specific CD8+ cells that could be expanded by boosting with an NY-ESO-1 vaccinia virus. The expanded cells could kill NY-ESO-1(157-165) peptide-pulsed targets in vivo. In order to examine the priming step directly, we constructed another lentiviral vector expressing the melanoma antigen Melan-A (MART-1). Here we show that Melan-A protein is also efficiently expressed after transduction of human DC cultured from peripheral blood mononuclear cells. When these transduced DC are co-cultured with autologous naïve T cells, they cause the expansion of cells that recognise the HLA-A2 restricted Melan-A(27-35) epitope. The expanded cells are functional in that they release IFN-gamma upon antigen stimulation. Melan-A lentiviral vector transduced DC caused a similar level of naïve T-cell expansion to Melan-A(27-35) peptide-pulsed DC in four experiments using different HLA-A2 positive donors. These data suggest that a vaccine based either on DC transduced with a lentiviral vector ex vivo, or on direct lentiviral vector injection, should be assessed in a phase I clinical trial.
Lopes
Luciene
L
Infection and Immunity, University College London, Windeyer Building, 46 Cleveland St, W1T 4JF, London, UK.
Fletcher
Kate
K
Ikeda
Yasuhiro
Y
Collins
Mary
M
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D015153:Blotting, Western; D019496:Cancer Vaccines; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D005822:Genetic Vectors / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007371:Interferon-gamma; D016086:Lentivirus / Q000235:genetics; D058965:MART-1 Antigen; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014161:Transduction, Genetic
D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D019496:Cancer Vaccines; D058965:MART-1 Antigen; C548667:MLANA protein, human; D008565:Membrane Proteins; C548668:Mlana protein, mouse; D009363:Neoplasm Proteins; D007371:Interferon-gamma