CTLA-4 blockade confers lymphocyte resistance to regulatory T-cells in advanced melanoma: Surrogate marker of efficacy of tremelimumab?

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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 lood leukocyte populations in association withTcell and regulatoryTcell (Treg) functions were evaluated. Results: Prior to therapy, patients with advanced melanoma presented with a severe CD4 + and CD8+ Tcell lymphopenia associated with blunted T-cell proliferative capacities that could be assigned toTreg. Tremelimumab rapidly restored the effector and memory CD4+ and CD8+ T-cell pool and TCR-dependent T-cell proliferation that became entirely resistant toTreg-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 toT reg-inhibitory effects (obtained in 7 of 10 patients). Conclusion: CTLA-4 blockade seems to be a valuable strategy to revive reactive memory Tcells anergized in the context of stage IV melanoma, and our work suggests that memory T-cell resistance toTreg resulting from anti - CTLA-4 treatment might be a biological activity marker for tremelimumab in patients with melanoma.© 2008 American Association for Cancer Research.

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Ménard, C., Ghiringhelli, F., Roux, S., Chaput, N., Mateus, C., Grohmann, U., … Robert, C. (2008). CTLA-4 blockade confers lymphocyte resistance to regulatory T-cells in advanced melanoma: Surrogate marker of efficacy of tremelimumab? Clinical Cancer Research, 14(16), 5242–5249. https://doi.org/10.1158/1078-0432.CCR-07-4797

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