Enhancement of interleukin-12 gene-based tumor immunotherapy by the reduced secretion of p40 subunit and the combination with farnesyltransferase inhibitor

Hum Gene Ther. 2005 Mar;16(3):328-38. doi: 10.1089/hum.2005.16.328.

Abstract

Interleukin-12 (IL-12) gene was shown to produce both IL-12 and p40 subunit. The excess production of the p40 subunit as a natural antagonist of IL-12 is a major obstacle of IL-12 gene-based cancer therapy. We previously reported that IL-12N220L gene, which selectively reduces the secretion of the p40 subunit, induces long-lasting stronger type 1 helper T cells (T(H)1) and cytotoxic T lymphocyte (CTL) immunity in hepatitis C virus (HCV) E2 DNA vaccination model and higher protection from challenge with tumor cells expressing E2 than IL-12 in a prophylactic setting. Here, we demonstrated that intratumoral injection of IL-12N220L-expressing adenovirus showed better tumor growth inhibition and higher survival rate than that of IL-12 or granulocyte macrophage-colony stimulating factor (GM-CSF)-expressing adenovirus in a therapeutic setting. In particular, the mice cured by IL-12N220L treatment were protected against intravenous rechallenge of the same tumor cells better than those by IL-12 treatment. In addition, the enhanced antitumor activity of IL-12N220L was confirmed in B16F10 lung metastasis model, which correlated with the frequency of tumor-specific interferon (IFN)-gamma-secreting cells. When tested in CT26/NP tumor that expresses influenza nucleoprotein (NP) as a tumor antigen, IL-12N220L induced stronger NP-specific T(H)1 and CTL responses than IL-12, particularly at a later time point, indicating the generating long-term tumor-specific memory T-cell responses. Moreover, the potent antitumor effects of IL-12N220L were further augmented by combination with chemotherapy using farnesyltransferase inhibitor (FTI), LB42908. Taken together, our results suggest that IL-12N220L is superior to IL-12 in cancer immunotherapy, which can be further enhanced by combination with chemotherapy.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Alkyl and Aryl Transferases / antagonists & inhibitors
  • Animals
  • Cell Line, Tumor
  • Drug Therapy, Combination
  • Farnesyltranstransferase
  • Genetic Therapy / methods*
  • Genetic Vectors / genetics
  • Imidazoles / therapeutic use*
  • Immunoenzyme Techniques / methods
  • Immunotherapy / methods*
  • Interferon-gamma / metabolism
  • Interleukin-12 / genetics
  • Interleukin-12 / metabolism
  • Interleukin-12 / therapeutic use*
  • Interleukin-12 Subunit p40
  • Mice
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • Nucleoproteins / metabolism
  • Piperazines / therapeutic use*
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Protein Subunits / therapeutic use*

Substances

  • Imidazoles
  • Interleukin-12 Subunit p40
  • LB42908
  • Nucleoproteins
  • Piperazines
  • Protein Subunits
  • Interleukin-12
  • Interferon-gamma
  • Alkyl and Aryl Transferases
  • Farnesyltranstransferase