Gene Therapy against Murine Melanoma B16F10-Nex2 Using IL-13Ralpha2-Fc Chimera and Interleukin 12 in Association with a Cyclopalladated Drug.
Interleukin 13 (IL-13) is immunoregulatory in many diseases, including cancer. The protective or suppressive role of CD1-restricted natural killer T cells (NKT cells) in tumor immunosurveillance and immunity is well documented. Interleukin 12 (IL-12) can activate type I NKT cells to produce interferon-gamma (IFN-gamma), whereas type II NKT cells may produce IL-13. The high-affinity chain of IL-13Ralpha2 may act as negative inhibitor, suppressing the action of IL-13 and helping to maintain tumor immunosurveillance. We constructed an mIL-13Ralpha2-Fc chimera in a eukaryotic expression vector and confirmed the identity of the recombinant protein by immunoblot analysis and binding to IL-13 in chemiluminescent ELISA. Such DNA vaccine was tested against syngeneic B16F10-Nex2 murine melanoma. In vivo experiments showed a protective effect mediated by high production of IFN-gamma and down-regulation of anti-inflammatory interleukins mainly by NKT 1.1(+) T cells. Biochemoterapy in vivo with plasmid encoding mIL-13Ralpha2-Fc in association with plasmid encoding IL-12 and the 7A cyclopalladated drug led to a significant reduction in the tumor evolution with 30% tumor-free mice. We conclude that IL-12 gene therapy, followed by continuous administration of IL-13Ralpha2-Fc gene along with 7A-drug has antitumor activity involving the high production of proinflammatory cytokines and low immune suppression, specifically by NK1.1(+)T cells producing IL-13 and IL-10.
Hebeler-Barbosa
Flavia
F
Unidade de Oncologia Experimental (UNONEX), Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.
Rodrigues
Elaine G
EG
Puccia
Rosana
R
Caires
Antonio Cf
AC
Travassos
Luiz R
LR
Int J Cancer. 2003 Nov 10;107(3):498-504
14506753
Cancer Res. 2005 Dec 15;65(24):11743-51
16357187
Nat Immunol. 2000 Dec;1(6):515-20
11101874
J Immunol. 2003 Feb 1;170(3):1197-201
12538676
J Immunol. 1998 Sep 1;161(5):2317-24
9725226
Immunity. 1998 Feb;8(2):255-64
9492006
J Immunol. 2000 Feb 1;164(3):1458-62
10640762
Nat Med. 2003 May;9(5):582-8
12669034
Nat Rev Immunol. 2003 Feb;3(2):133-46
12563297
Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13020-5
12232042
J Immunol. 1999 Jan 15;162(2):920-30
9916716
J Immunol. 1994 Feb 1;152(3):1094-102
7507958
Cancer Res. 1975 Jan;35(1):218-24
1109790
Mol Ther. 2002 Jun;5(6):668-75
12027550
Int J Cancer. 2005 Mar 10;114(1):80-7
15523692
Proc Natl Acad Sci U S A. 2004 Jan 13;101(2):586-90
14699044
J Exp Med. 1998 Jul 20;188(2):287-96
9670041
J Exp Med. 2005 Dec 19;202(12):1627-33
16365146
Nat Med. 2006 Jan;12(1):99-106
16327802
Cytokines Cell Mol Ther. 2002;7(3):107-16
12850810
Nature. 1993 Mar 18;362(6417):248-50
8096327
Science. 1998 Dec 18;282(5397):2261-3
9856950
J Exp Med. 2000 Feb 21;191(4):661-8
10684858
J Biol Chem. 1996 Nov 15;271(46):29265-70
8910586
J Exp Med. 2005 Nov 7;202(9):1279-88
16275765
J Exp Med. 2002 Mar 4;195(5):625-36
11877485
Science. 1998 Dec 18;282(5397):2258-61
9856949
J Exp Med. 2002 Mar 4;195(5):637-41
11877486
Hybridoma. 1996 Dec;15(6):415-22
8985752
J Immunol. 2004 Jun 15;172(12):7368-76
15187113
J Exp Med. 1993 Oct 1;178(4):1223-30
8104230
Science. 1997 Nov 28;278(5343):1623-6
9374462
Trends Immunol. 2007 Nov;28(11):491-6
17964217
Int Immunol. 2004 Jul;16(7):1009-17
15184346
Immunol Today. 1994 Jan;15(1):19-26
7907877
J Immunol. 1996 May 1;156(9):3366-73
8617962
Cancer Res. 2006 Apr 1;66(7):3869-75
16585215
J Immunol. 1999 Sep 1;163(5):2387-91
10452972
Microbiology (Reading). 2002 Aug;148(Pt 8):2607-2615
12177355
J Exp Med. 1982 Jun 1;155(6):1823-41
6176669
Nat Med. 2006 Jan;12(1):13-4
16397542
Annu Rev Immunol. 2003;21:425-56
12615888
Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6291-6
8692808
J Immunol. 1999 Jan 1;162(1):78-87
9886372
Immunol Today. 1996 Mar;17(3):108-10
8820266
J Clin Invest. 2007 Nov;117(11):3169-72
17975660
J Immunol. 2000 Sep 1;165(5):2665-70
10946296
Cancer Immunol Immunother. 2008 Jun;57(6):907-12
18004566
Proc Natl Acad Sci U S A. 1993 May 15;90(10):4455-9
8506285
J Immunol. 2007 Oct 15;179(8):5126-36
17911598
Nat Rev Immunol. 2004 Mar;4(3):231-7
15039760
Blood. 2002 Feb 15;99(4):1259-66
11830474
Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):497-501
8552669
Cancer Res. 2003 Jun 15;63(12):3058-60
12810627
J Exp Med. 1999 Apr 5;189(7):1121-8
10190903
J Immunol. 1992 Aug 15;149(4):1211-5
1386860
J Immunol. 1995 Jan 15;154(2):799-803
7529288
J Exp Med. 2003 Dec 1;198(11):1741-52
14657224
J Immunol. 2002 Nov 15;169(10):5796-804
12421960
Annu Rev Immunol. 1989;7:145-73
2523712
J Allergy Clin Immunol. 2003 Apr;111(4):720-8
12704349
Cytokine Growth Factor Rev. 2002 Apr;13(2):155-68
11900991
Blood. 2001 May 1;97(9):2673-9
11313257
Nat Rev Immunol. 2003 Aug;3(8):630-41
12974478
J Exp Med. 2002 Jul 1;196(1):119-27
12093876