NK cells and CD8+ T cells cooperate to improve therapeutic responses in melanoma treated with CTLA-4 blockade and IL-2 (TUM2P.1039)

• Published in: The Journal of immunology (1950) 2015-05, Vol.194 (1_Supplement), p.69-69.36
• Main Authors: Kohlhapp, Frederick, Broucek, Joseph, Hughes, Tasha, Huelsmann, Erica, Zloza, Andrew, Kaufman, Howard
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.194.Supp.69.36

Immunotherapy is a promising approach for the treatment of metastatic melanoma and combination strategies may have potential for improving therapeutic responses. CTLA-4 blockade increases the CD8:Treg ratio in the tumor microenvironment and IL-2 promotes NK and CD8+ T cell function. Thus, we hypothesized combination IL-2 and CTLA-4 blockade would result in improved anti-tumor responses. This hypothesis was confirmed utilizing the poorly immunogenic B16 melanoma model, with CTLA-4 blocking antibody on days 3, 6, and 9 and/or IL-2 twice daily on days 4-8 after challenge, mirroring clinical use of these agents. Combination immunotherapy resulted in delayed tumor growth and prolonged survival compared to either monotherapy. Depletion studies suggested that both CD8+ T and NK cells were required for the therapeutic effects. In this model, combination treatment resulted in fewer tumor-infiltrating CD8+ T and NK cells but more infiltrating Tregs in the tumor microenvironment when compared to monotherapy CTLA-4 blockade. Further, IL-2 therapy was associated with a reduction in the proportion of highly differentiated/exhausted NK cells in the tumor microenvironment. No significant toxicity was observed in the mice. These results support the combination of IL-2 and CTLA-4 blockade in melanoma and a clinical trial based on these data has been initiated.