Enhancement of interleukin-12 gene-based tumor immunotherapy by the reduced secretion of p40 subunit and the combination with farnesyltransferase inhibitor.
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.
Jin
Hyun-Tak
HT
National Research Laboratory, Department of Life Science, Pohang University of Science & Technology, Pohang 790-784, Korea.
Youn
Je-In
JI
Kim
Hye-Ju
HJ
Lee
Jee-Boung
JB
Ha
Sang-Jun
SJ
Koh
Jong Sung
JS
Sung
Young-Chul
YC
D000256:Adenoviridae / Q000235:genetics; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000818:Animals; D045744:Cell Line, Tumor; D004359:Drug Therapy, Combination; D051231:Farnesyltranstransferase; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D007093:Imidazoles / Q000627:therapeutic use*; D007124:Immunoenzyme Techniques / Q000379:methods; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D053762:Interleukin-12 Subunit p40; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D009698:Nucleoproteins / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*
D007093:Imidazoles; D053762:Interleukin-12 Subunit p40; C448382:LB42908; D009698:Nucleoproteins; D010879:Piperazines; D021122:Protein Subunits; D018664:Interleukin-12; D007371:Interferon-gamma; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase