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

Abstract

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.