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Agonist Anti-GITR Antibody Enhances Vaccine-Induced CD8⁺ T-Cell Responses and Tumor Immunity

¹ Swim Across America Laboratory of Tumor Immunology, Memorial Sloan-Kettering Cancer Center; ² Department of Medicine, Weill Cornell Medical University, New York, New York; ³ Dartmouth-Hitchcock Medical Center, Hanover, New Hampshire; ⁴ National Cancer Institute, NIH, Bethesda, Maryland; and ⁵ Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan

Requests for reprints: Adam Cohen, Swim Across America Laboratory of Tumor Immunology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: 212-639-5165; Fax: 212-717-3342; E-mail: cohena{at}mskcc.org.

Immunization of mice with plasmids encoding xenogeneic orthologues of tumor differentiation antigens can break immune ignorance and tolerance to self and induce protective tumor immunity. We sought to improve on this strategy by combining xenogeneic DNA vaccination with an agonist anti–glucocorticoid-induced tumor necrosis factor receptor family–related gene (GITR) monoclonal antibody (mAb), DTA-1, which has been shown previously both to costimulate activated effector CD4⁺ and CD8⁺ T cells and to inhibit the suppressive activity of CD4⁺CD25⁺ regulatory T cells. We found that ligation of GITR with DTA-1 just before the second, but not the first, of 3 weekly DNA immunizations enhanced primary CD8⁺ T-cell responses against the melanoma differentiation antigens gp100 and tyrosinase-related protein 2/dopachrome tautomerase and increased protection from a lethal challenge with B16 melanoma. This improved tumor immunity was associated with a modest increase in focal autoimmunity, manifested as autoimmune hypopigmentation. DTA-1 administration on this schedule also led to prolonged persistence of the antigen-specific CD8⁺ T cells as well as to an enhanced recall CD8⁺ T-cell response to a booster vaccination given 4 weeks after the primary immunization series. Giving the anti-GITR mAb both during primary immunization and at the time of booster vaccination increased the recall response even further. Finally, this effect on vaccine-induced CD8⁺ T-cell responses was partially independent of CD4⁺ T cells (both helper and regulatory), consistent with a direct costimulatory effect on the effector CD8⁺ cells themselves. (Cancer Res 2006; 66(9); 4904-12)

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