Details

Autor(en) / Beteiligte

• Putzer, Brigitte M.
• Hitt, Mary
• Muller, William J.
• Emtage, Peter
• Gauldie, Jack
• Graham, Frank L.

Titel

Interleukin 12 and B7-1 Costimulatory Molecule Expressed by an Adenovirus Vector Act Synergistically to Facilitate Tumor Regression

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 1997-09, Vol.94 (20), p.10889-10894

Ort / Verlag

United States: National Academy of Sciences of the United States of America

Erscheinungsjahr

1997

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 × 107pfu/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.