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CTLA-4 Blockade Confers Lymphocyte Resistance to Regulatory T-Cells in Advanced Melanoma: Surrogate Marker of Efficacy of Tremelimumab?

Authors' Affiliations: ¹ Center of Clinical Investigations, CBT507, ² Institut National de la Sante et de la Recherche Medicale U805, and ³ Department of Medicine, Dermatology Unit, Institut Gustave Roussy, Villejuif, France; ⁴ Department of Medicine, Centre Georges Francois Leclerc, ⁵ CRI Institut National de la Sante et de la Recherche Medicale 866, Faculté de Médecine, Dijon, France; ⁶ Department of Experimental Medicine, University of Perugia, Perugia, Italy; and ⁷ Institut National de la Sante et de la Recherche Medicale U561, Hôpital St. Vincent de Paul, Paris, France

Requests for reprints: François Ghiringhelli, CRI866 Faculté de Médecine, 7 Boulevard Jeanne d'Arc, 21000 Dijon, France. Phone: 33-38039-3353; Fax: 33-38039-3434; E-mail: francois.ghiringhelli{at}yahoo.fr.

Purpose: Anti–CTL antigen-4 (CTLA-4) monoclonal antibody (mAb) has led to encouraging antitumor activity associated with immune-related adverse events in patients with heavily pretreated melanoma. However, mechanisms of action and surrogate immunologic markers of efficacy have not been reported thus far.

Experimental Design: We monitored the immune responses of 10 melanoma patients included in a phase II clinical trial, which evaluated the efficacy of a second line of therapy of tremelimumab anti–CTLA-4 mAb in patients with metastatic melanoma. The frequency of blood leukocyte populations in association with T cell and regulatory T cell (T_reg) functions were evaluated.

Results: Prior to therapy, patients with advanced melanoma presented with a severe CD4⁺ and CD8⁺ T cell lymphopenia associated with blunted T-cell proliferative capacities that could be assigned to T_reg. Tremelimumab rapidly restored the effector and memory CD4⁺ and CD8⁺ T-cell pool and TCR-dependent T-cell proliferation that became entirely resistant to T_reg-mediated suppression. Progression-free survival and overall survival was directly correlated with the acquisition of a biological response defined as the resistance of peripheral lymphocytes to T_reg-inhibitory effects (obtained in 7 of 10 patients).

Conclusion: CTLA-4 blockade seems to be a valuable strategy to revive reactive memory T cells anergized in the context of stage IV melanoma, and our work suggests that memory T-cell resistance to T_reg resulting from anti–CTLA-4 treatment might be a biological activity marker for tremelimumab in patients with melanoma.