CpG immunostimulatory oligodeoxynucleotide 1826 enhances antitumor effect of interleukin 12 gene-modified tumor vaccine in a melanoma model in mice.
OBJECTIVE
The effectiveness of interleukin (IL)-12-secreting tumor vaccines in the treatment of mouse tumors could be enhanced by concurrent application of cytokines and costimulatory molecules. We investigated the therapeutic potential of IL-12 gene-transduced melanoma vaccine in combination with CpG immunostimulatory oligodeoxynucleotide (ODN) 1826, an adjuvant known to favor development of Th1-biased immune response, in a B78-H1 (B78) melanoma model in mice.


METHODS
Mice injected with B78 melanoma cells were treated with irradiated IL-12 gene-transduced B78 cells [B78/IL-12(X)] and/or ODN 1826. Mechanisms responsible for the antitumor effects of the treatment were investigated using fluorescence-activated cell sorter analysis, a standard (51)Cr releasing assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and ELISA.


RESULTS
Single injection of B78/IL-12(X) cells had no effect on tumor growth, whereas seven consecutive daily injections of ODN 1826 markedly inhibited tumor progression with occasional curative effects. When used in combination, B78/IL-12(X) cells and ODN 1826 caused additional tumor growth reduction and eradication of tumors in 62% of treated mice. The combined treatment activated local inflammatory response against tumor but also induced systemic antitumor immunity. In vitro studies have shown that when used together, B78/IL-12(X) cells and ODN 1826 induced a potent Th1 response and suggested the role of IFN-gamma in activation of the host immune response. The antitumor effects in double-treated mice were accompanied by the development of cytotoxic effectors in the spleen and activation of macrophages.


CONCLUSIONS
The results provided the evidence that the combination of IL-12 gene-modified melanoma vaccine and ODN 1826 induces synergistically systemic and local antitumor immunity.
Switaj
Tomasz
T
Department of Immunology, Center of Biostructure, Medical University of Warsaw, Warsaw, Poland. tswitaj@ib.amwaw.edu.pl
Jalili
Ahmad
A
Jakubowska
Anna B
AB
Drela
Nadzieja
N
Stoksik
Magdalena
M
Nowis
Dominika
D
Basak
Grzegorz
G
Golab
Jakub
J
Wysocki
Piotr J
PJ
Mackiewicz
Andrzej
A
Sasor
Agata
A
Socha
Koryna
K
Jakóbisiak
Marek
M
Lasek
Witold
W
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D018899:CpG Islands; D016207:Cytokines / Q000096:biosynthesis; D004247:DNA / Q000494:pharmacology*; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005456:Fluorescent Dyes / Q000494:pharmacology; D000949:Histocompatibility Antigens Class II / Q000737:chemistry; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics* / Q000378:metabolism*; D008207:Lymphatic Metastasis; D008264:Macrophages / Q000378:metabolism; D008545:Melanoma / Q000235:genetics*; D008546:Melanoma, Experimental / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides; D009841:Oligonucleotides / Q000737:chemistry*; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013778:Tetrazolium Salts / Q000494:pharmacology; D018417:Th1 Cells; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors
D000970:Antineoplastic Agents; D019496:Cancer Vaccines; C423449:CpG ODN 1826; D016207:Cytokines; D005456:Fluorescent Dyes; D000949:Histocompatibility Antigens Class II; D009838:Oligodeoxyribonucleotides; D009841:Oligonucleotides; D013778:Tetrazolium Salts; D013844:Thiazoles; D018664:Interleukin-12; D007371:Interferon-gamma; D004247:DNA; C022616:thiazolyl blue