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.
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.
Chen
L
L
Dana-Farber Cancer Institute, Department of Urology, Harvard Medical School, Boston, MA 02115, USA.
Chen
D
D
Block
E
E
O'Donnell
M
M
Kufe
D W
DW
Clinton
S K
SK
D000256:Adenoviridae; D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D002277:Carcinoma / Q000235:genetics* / Q000276:immunology / Q000628:therapy; D018076:DNA, Complementary / Q000008:administration & dosage / Q000235:genetics*; D015316:Genetic Therapy; D005822:Genetic Vectors; D007109:Immunity; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D051379:Mice; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy; D014162:Transfection; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000276:immunology / Q000628:therapy
D000276:Adjuvants, Immunologic; D018076:DNA, Complementary; D018664:Interleukin-12