title: Conditional interleukin-12 gene therapy promotes safe and effective antitumor immunity.
abstract: We and others have previously demonstrated that (chronic) interleukin (IL)-12 gene therapy delivered intratumorally through ex vivo gene-engineered dendritic cell (DC) is competent to promote the regression of established murine tumors. In this report, we have developed a conditional expression system (rAd.RheoIL12) to determine the temporal requirements of transgenic IL-12p70 production by administered DC on therapeutic outcome in a subcutaneous B16 melanoma model. DCs infected with rAd.RheoIL12 (DC.RheoIL12) secreted IL-12p70 in a tightly regulated fashion in response to a synthetic diacylhydrazine small molecule ligand in vitro, and the treatment benefit of DC.RheoIL12 delivered into B16 lesions was strictly ligand dependent in vivo. Indeed, DC.RheoIL12-based therapy promoted the regression of established day 7 B16 tumor lesions after intratumoral injection, provided that ligand administration occurred within 24 h of DC injection and was sustained for approximately 5 or more days. Treatment efficacy was correlated to the magnitude of systemic anti-B16 CD8(+) T cells cross-primed in vivo, which in turn, appeared dependent on the early enhanced in vivo survival of adoptively transferred DC.RheoIL12 in tumor and tumor-draining lymph nodes. The unique safety feature of DC.RheoIL12 application was emphasized in a combined treatment model with rIL-2, where profound TNF-alpha-associated toxicity could be ameliorated upon discontinuation of activating ligand administration.
authors.affiliation: Department of Dermatology, University of Pittsburgh School of Medicine, PA 15213, USA.
authors.forename: H
authors.initials: H
authors.lastname: Komita
authors.forename: X
authors.initials: X
authors.lastname: Zhao
authors.forename: A K
authors.initials: AK
authors.lastname: Katakam
authors.forename: P
authors.initials: P
authors.lastname: Kumar
authors.forename: M
authors.initials: M
authors.lastname: Kawabe
authors.forename: H
authors.initials: H
authors.lastname: Okada
authors.forename: J M
authors.initials: JM
authors.lastname: Braughler
authors.forename: W J
authors.initials: WJ
authors.lastname: Storkus
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D016219:Immunotherapy, Adoptive / Q000379:methods; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D018417:Th1 Cells / Q000276:immunology
chemical_list: D018664:Interleukin-12