Regression of colon cancer and induction of antitumor immunity by intratumoral injection of adenovirus expressing interleukin-12.
Interleukin-12 (IL-12) has been shown to possess potent immunoregulatory and antitumoral effects. We have evaluated the anti-oncogenic potential and the mechanisms of the antitumoral effect of in vivo adenovirus-mediated transfer of IL-12 gene in a murine model of colon cancer. AdCMVIL-12 was constructed to permit coordinated production of p40 and p35 subunits of IL-12 gene to obtain the maximum IL-12 bioactivity. Infection of murine colon cancer CT-26 cells in vitro with AdCMVIL-12 resulted in the production of high levels of IL-12. In vivo gene therapy of colon cancer nodules by intratumoral injection of AdCMVIL-12 induced a local increase in IL-12 and interferon-gamma levels and a complete regression of the tumor in 26 of 34 (76%) mice. Tumor disappeared between days 7 and 10 after vector administration. The antitumoral effect was mediated by CD8+ T cells and was associated with the generation of cytotoxic T lymphocytes against colon cancer cells. Animals that eliminated the tumor were protected against a second administration of neoplastic cells. Treatment with AdCMVIL-12 of one tumor nodule also caused regression of established tumors at distant sites. These data demonstrate that AdCMVIL-12 is a useful therapeutic tool for established colon cancer in mice and should be considered for application in humans.
Mazzolini
G
G
Department of Medicine, School of Medicine and Clinica Universitaria, University of Navarra, Pamplona, Spain.
Qian
C
C
Xie
X
X
Sun
Y
Y
Lasarte
J J
JJ
Drozdzik
M
M
Prieto
J
J
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy*; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D015552:Injections, Intralesional; D007371:Interferon-gamma / Q000235:genetics; D018664:Interleukin-12 / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D018664:Interleukin-12; D007371:Interferon-gamma