Adjuvanticity of plasmid DNA encoding cytokines fused to immunoglobulin Fc domains Journal Article


Authors: Ferrone, C. R.; Perales, M. A.; Goldberg, S. M.; Somberg, C. J.; Hirschhorn-Cymerman, D.; Gregor, P. D.; Turk, M. J.; Ramirez-Montagut, T.; Gold, J. S.; Houghton, A. N.; Wolchok, J. D.
Article Title: Adjuvanticity of plasmid DNA encoding cytokines fused to immunoglobulin Fc domains
Abstract: Purpose: Plasmid DNAs encoding cytokines enhance immune responses to vaccination in models of infectious diseases and cancer. We compared DNA adjuvants for their ability to enhance immunity against a poorly immunogenic self-antigen expressed by cancer. Experimental Design: DNAs encoding cytokines that affect T cells [interleukin (IL)-2, IL-12, IL-15, IL-18, IL-21, and the chemokine CCL21] and antigen-presenting cells [granulocyte macrophage colony-stimulating factor (GM-CSF)] were compared in mouse models as adjuvants to enhance CD8 + T-cell responses and tumor immunity. A DNA vaccine against a self-antigen, gp100, expressed by melanoma was used in combination with DNA encoding cytokines and cytokines fused to the Fc domain of mouse IgG1 (Ig). Results: We found that (a) cytokine DNAs generally increased CD8 + T-cell responses against gp100; (b) ligation to Fc domains further enhanced T-cell responses; (c) adjuvant effects were sensitive to timing of DNA injection; (d) the most efficacious individual adjuvants for improving tumor-free survival were IL-12/Ig, IL-15/Ig, IL-21/Ig, GM-CSF/Ig, and CCL21; and (e) combinations of IL-2/Ig + IL-12/Ig, IL-2/Ig + IL-15/Ig, IL-12/Ig + IL-15/Ig, and IL-12/Ig + IL-21/Ig were most active; and (f) increased adjuvanticity of cytokine/Ig fusion DNAs was not related to higher tissue levels or greater stability. Conclusions: These observations support the potential of cytokine DNA adjuvants for immunization against self-antigens expressed by cancer, the importance of timing, and the enhancement of immune responses by Fc domains through mechanisms unrelated to increased half-life. © 2006 American Association for Cancer Research.
Keywords: cancer survival; controlled study; protein expression; survival analysis; nonhuman; neoplasms; antigen expression; cd8+ t lymphocyte; t lymphocyte; t-lymphocytes; mouse; animals; mice; animal tissue; glycoprotein gp 100; interleukin 2; melanoma; granulocyte macrophage colony stimulating factor; interleukin 21; animal experiment; animal model; xenograft model antitumor assays; mice, inbred c57bl; time factors; cytokine; cytokines; recombinant gamma interferon; immunogenicity; cancer immunization; autoantigens; tumor immunity; plasmids; autoimmunity; dna vaccine; drug blood level; graft rejection; immunoglobulin g1; adjuvants, immunologic; tumor rejection; vaccines, dna; antigen presenting cell; interleukin 12; interleukin 15; antigens, cd8; hypopigmentation; plasmid dna; immunization; interleukin 18; immunoglobulin fc fragments; vitiligo; secondary lymphoid tissue chemokine; interleukin-12; immunoglobulin fc fragment; immunotherapy, active; acute-phase reaction
Journal Title: Clinical Cancer Research
Volume: 12
Issue: 18
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2006-09-15
Start Page: 5511
End Page: 5519
Language: English
DOI: 10.1158/1078-0432.ccr-06-0979
PUBMED: 17000687
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 23" - "Export Date: 4 June 2012" - "CODEN: CCREF" - "Source: Scopus"
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