Eradication of murine bladder carcinoma by intratumor injection of a bicistronic adenoviral vector carrying cDNAs for the IL-12 heterodimer and its inhibition by the IL-12 p40 subunit homodimer.

Abstract

IL-12 is a heterodimeric immunoregulatory cytokine composed of covalently linked p40 and p35 subunits and exhibits antitumor activity in a variety of laboratory models. The efficacy of systemically administered cytokines for cancer therapy is often limited by toxicity. The gene therapy approach provides a mechanism to achieve temporary and high local concentrations of cytokines within a tumor with less risk of systemic toxicity. We constructed replication-defective adenoviruses containing the murine IL-12 p40 subunit (Ad.mp40) or a bicistronic vector containing cDNAs for the p40 and p35 subunits (Ad.mIL-12). Murine MB49 bladder cancer cells infected with Ad.mIL-12 secrete high concentrations of biologically active IL-12, while those infected with Ad.mp40 produce the p40 homodimer. Tumors injected with Ad.mIL-12 show rapid increases in IL-12 and IFN-gamma expression over 2 to 5 days and a return to baseline by 7 to 14 days. Injection of tumors with Ad.mIL-12 (1 x 10(9) plaque-forming units) results in a complete tumor regression in all mice, while those treated with control adenovirus succumb to their tumor. Efficacy is reduced when studies are performed in mice depleted of CD4+ and CD8+ cells or in nude mice. Mice cured of their tumor by Ad.mIL-12 demonstrate specific protective immunity upon rechallenge. Ad.mp40 does not exhibit antitumor activity and may antagonize the activity of rIL-12 or Ad.mIL-12. In summary, gene therapy strategies for cancer using adenoviral vectors containing IL-12 are highly effective with no significant toxicity in mice.

• Authors: L Chen, D Chen, E Block, M O'Donnell, D W Kufe, S K Clinton
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 159 Issue 1 Pg. 351-9 (Jul 01 1997) ISSN: 0022-1767 [Print] United States
• PMID: 9200473 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adjuvants, Immunologic
• DNA, Complementary
• Interleukin-12

Topics

• Adenoviridae
• Adjuvants, Immunologic (biosynthesis, genetics)
• Animals
• Carcinoma (genetics, immunology, therapy)
• DNA, Complementary (administration & dosage, genetics)
• Genetic Therapy
• Genetic Vectors
• Immunity
• Interleukin-12 (biosynthesis, genetics, immunology)
• Mice
• Neoplasms, Experimental (genetics, immunology, therapy)
• Transfection
• Urinary Bladder Neoplasms (genetics, immunology, therapy)