Direct intratumoral injection of an adenovirus expressing interleukin-12 induces regression and long-lasting immunity that is associated with highly localized expression of interleukin-12.
Mice bearing breast tumors were treated with a single dose of an adenovirus expressing interleukin-12 (AdmIL-12.1) injected intratumorally, which produced regressions in greater than 75% of the treated tumors; approximately one-third of the animals remained tumor free. Complete regression was associated with immunity to secondary challenge with fresh tumor cells. Analysis of local cytokine expression demonstrated maximum expression of IL-12 within the tumor between 24 and 72 hr post-injection, reaching 600-800 ng per tumor, with elevated local levels of IL-12 detectable for at least 9 days. This expression was highly localized as serum IL-12 peaked at 40-60 ng/ml at 24 hr and was less than 10 ng/ml from day 3 onward. Interferon-gamma (IFN-gamma) concentrations were markedly increased within the tumor following AdmIL-12.1 administration, demonstrating that IL-12 was acting locally. Tumor-draining lymph node cells spontaneously produced IFN-gamma following AdmIL-12.1 treatment, suggesting these cells were activated by IL-12. These data demonstrate that AdmIL-12.1 can be used to deliver very high levels of localized cytokine production. Moreover, we have confirmed that the IL-12 produced from our vector actually affects the local cytokine environment of the tumor and activates responder cells present within the tumor.
Bramson
J L
JL
Department of Biology, McMaster University, Hamilton, Ontario.
Hitt
M
M
Addison
C L
CL
Muller
W J
WJ
Gauldie
J
J
Graham
F L
FL
D000260:Adenoviruses, Human / Q000235:genetics*; D000818:Animals; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000235:genetics* / Q000276:immunology / Q000627:therapeutic use*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D015674:Mammary Neoplasms, Animal / Q000628:therapy*; D051379:Mice
D018664:Interleukin-12; D007371:Interferon-gamma