title: Interleukin 12 and B7-1 costimulatory molecule expressed by an adenovirus vector act synergistically to facilitate tumor regression.
abstract: Stimulation of antitumor immune mechanisms is the primary goal of cancer immunotherapy, and accumulating evidence suggests that effective alteration of the host-tumor relationship involves immunomodulating cytokines and also the presence of costimulatory molecules. To examine the antitumor effect of direct in vivo gene transfer of murine interleukin 12 (IL-12) and B7-1 into tumors, we developed an adenovirus (Ad) vector, AdIL12-B7-1, that encodes the two IL-12 subunits in early region 1 (E1) and the B7-1 gene in E3 under control of the murine cytomegalovirus promoter. This vector expressed high levels of IL-12 and B7-1 in infected murine and human cell lines and in primary murine tumor cells. In mice bearing tumors derived from a transgenic mouse mammary adenocarcinoma, a single intratumoral injection with a low dose (2.5 x 10(7) pfu/mouse) of AdIL12-B7-1 mediated complete regression in 70% of treated animals. By contrast, administration of a similar dose of recombinant virus encoding IL-12 or B7-1 alone resulted in only a delay in tumor growth. Interestingly, coinjection of two different viruses expressing either IL-12 or B7-1 induced complete tumor regression in only 30% of animals treated at this dose. Significantly, cured animals remained tumor free after rechallenge with fresh tumor cells, suggesting that protective immunity had been induced by treatment with AdIL12-B7-1. These results support the use of Ad vectors as a highly efficient delivery system for synergistically acting molecules and show that the combination of IL-12 and B7-1 within a single Ad vector might be a promising approach for in vivo cancer therapy.
authors.affiliation: Department of Biology, McMaster University, 1280 Main Street West, Hamilton, ON Canada L8S 4K1.
authors.forename: B M
authors.initials: BM
authors.lastname: Pützer
authors.forename: M
authors.initials: M
authors.lastname: Hitt
authors.forename: W J
authors.initials: WJ
authors.lastname: Muller
authors.forename: P
authors.initials: P
authors.lastname: Emtage
authors.forename: J
authors.initials: J
authors.lastname: Gauldie
authors.forename: F L
authors.initials: FL
authors.lastname: Graham
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000502:physiology*; D002461:Cell Line, Transformed; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D015552:Injections, Intralesional; D018664:Interleukin-12 / Q000235:genetics / Q000502:physiology*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D018122:B7-1 Antigen; D018664:Interleukin-12