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

Hum Gene Ther. 1996 Oct 20;7(16):1995-2002. doi: 10.1089/hum.1996.7.16-1995.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviruses, Human / genetics*
  • Animals
  • Female
  • Gene Expression
  • Genetic Therapy*
  • Genetic Vectors*
  • Interferon-gamma / biosynthesis
  • Interleukin-12 / genetics*
  • Interleukin-12 / immunology
  • Interleukin-12 / therapeutic use*
  • Lymph Nodes / cytology
  • Lymph Nodes / immunology
  • Mammary Neoplasms, Animal / therapy*
  • Mice

Substances

  • Interleukin-12
  • Interferon-gamma