Adenoviral-mediated, intratumor gene transfer of interleukin 23 induces a therapeutic antitumor response.
Interleukin 23 (IL-23) is a member of the IL-12 family of heterodimeric cytokines, composed of p19 and p40 subunits, which exhibits immunostimulatory properties similar to IL-12. IL-23 has been shown to possess potent antitumor activities in several establishment models of cancer and a few therapeutic models, but the efficacy of local, adenoviral-mediated expression of IL-23 in established tumors has yet to be investigated. Here we have examined the antitumor activity of adenovirally delivered IL-23 in a day-7 MCA205 murine fibrosarcoma tumor model. Three intratumoral injections of adenovirus expressing IL-23 (Ad.IL-23) significantly increased animal survival and resulted in complete rejection of 40% of tumors, with subsequent generation of protective immunity and MCA205-specific cytotoxic T lymphocytes. In addition, we have shown that the antitumor activity of IL-23 is independent of IL-17, perforin and Fas ligand, but dependent on interferon-gamma, CD4(+) and CD8(+) T cells. These results demonstrate that direct intratumoral injection of adenovirus expressing IL-23 results in enhanced survival, tumor eradication and generation of protective immunity by generation of a Th1-type immune response.
Reay
J
J
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Kim
S-H
SH
Lockhart
E
E
Kolls
J
J
Robbins
P D
PD
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D053222:Fas Ligand Protein / Q000276:immunology; D005260:Female; D005354:Fibrosarcoma / Q000235:genetics / Q000276:immunology / Q000628:therapy* / Q000821:virology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis; D053759:Interleukin-23 / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D053208:Kaplan-Meier Estimate; D051379:Mice; D008810:Mice, Inbred C57BL; D054353:Perforin / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014161:Transduction, Genetic
D053222:Fas Ligand Protein; D020381:Interleukin-17; D053759:Interleukin-23; D054353:Perforin; D007371:Interferon-gamma