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Adjuvanticity of Plasmid DNA Encoding Cytokines Fused to Immunoglobulin Fc Domains

Authors' Affiliations: ¹ The Swim Across America Laboratory, Memorial Sloan-Kettering Cancer Center; ² Weill Medical and Graduate Schools of Cornell University, New York, New York; and ³ Dartmouth-Hitchcock Medical Center, Hanover, New Hampshire

Requests for reprints: Jedd D. Wolchok, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: 212-639-6570; Fax: 212-794-4352; E-mail: wolchokj{at}mskcc.org.

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.

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