Intratumoral IL-18 gene transfer improves therapeutic efficacy of antibody-targeted superantigen in established murine melanoma.
Antibody-targeted superantigen C215Fab-SEA is a fusion protein of staphylococcal enterotoxin A (SEA) and the Fab region of the tumor-reactive C215 mAb. It can trigger CTL against C215 antigen-positive tumor cells and induce tumor-suppressive cytokines. However, the antitumor effect of C215Fab-SEA is not satisfactory because of suboptimal production of Th1 cytokines after repeated administration. Interleukin 18 (IL-18) is a novel cytokine with profound effects on Th1 cellular response. In this study, we showed that adenovirus-mediated intratumoral IL-18 gene transfer strongly improved the therapeutic efficacy of C215Fab-SEA in the pre-established C215 antigen-expressing B16 melanoma murine model. More significant tumor inhibition and prolonged survival time were observed in tumor-bearing mice received combined therapy of C215Fab-SEA and Ad IL-18 than those of mice treated with C215Fab-SEA or AdIL-18 alone. Combination therapy augmented NK and CTL activities of tumor-bearing mice more markedly. The production of IL-2 and IFN-gamma also increased more significantly. More potent antitumor effect of combined therapy was observed in IL-10 KO mice with enhanced Th1 response. Our data demonstrated that the antitumor effect of C215Fab-SEA immunotherapy could be potentiated significantly by combination with intratumoral IL-18 gene transfer through more efficient activation of Th1 immune responses.
Wang
Q
Q
Institute of Immunology, Zhejiang University, 353 Yan'an Road, Hangzhou, 310031, PR China.
Yu
H
H
Ju
D W
DW
He
L
L
Pan
J P
JP
Xia
D J
DJ
Zhang
L H
LH
Cao
X
X
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D003131:Combined Modality Therapy; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D004768:Enterotoxins / Q000276:immunology; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D020382:Interleukin-18 / Q000235:genetics* / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D013154:Spleen / Q000276:immunology; D013211:Staphylococcus aureus / Q000276:immunology; D018089:Superantigens / Q000276:immunology / Q000627:therapeutic use*; D015996:Survival Rate; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D000951:Antigens, Neoplasm; D016207:Cytokines; D004768:Enterotoxins; D007140:Immunoglobulin Fab Fragments; D020382:Interleukin-18; D011993:Recombinant Fusion Proteins; D018089:Superantigens; C026066:enterotoxin A, Staphylococcal