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

Hyun Tak Jin, Je In Youn, Hye Ju Kim, Jee Boung Lee, Sang Jun Ha, Sung Koh Jong, Young Chul Sung

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

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 H1) 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)-γ-secreting cells. When tested in CT26/NP tumor that expresses influenza nucleoprotein (NP) as a tumor antigen, IL-12N220L induced stronger NP-specific TH1 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.

Original languageEnglish
Pages (from-to)328-338
Number of pages11
JournalHuman Gene Therapy
Volume16
Issue number3
DOIs
Publication statusPublished - 2005 Mar

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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