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 (Treg) 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 Treg. Tremelimumab rapidly restored the effector and memory CD4+ and CD8+ T-cell pool and TCR-dependent T-cell proliferation that became entirely resistant to Treg-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 Treg-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 Treg resulting from anti-CTLA-4 treatment might be a biological activity marker for tremelimumab in patients with melanoma.

• Authors: Cédric Ménard, François Ghiringhelli, Stephan Roux, Nathalie Chaput, Christine Mateus, Ursula Grohmann, Sophie Caillat-Zucman, Laurence Zitvogel, Caroline Robert
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 16 Pg. 5242-9 (Aug 15 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18698043 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antigens, CD
• Antineoplastic Agents
• Biomarkers
• CTLA-4 Antigen
• CTLA4 protein, human
• tremelimumab

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal (therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antigens, CD (drug effects, metabolism)
• Antineoplastic Agents (therapeutic use)
• Biomarkers (analysis)
• CTLA-4 Antigen
• Cell Proliferation (drug effects)
• Female
• Flow Cytometry
• Humans
• Immunologic Memory (drug effects)
• Lymphocyte Activation (drug effects)
• Male
• Melanoma (drug therapy, immunology)
• Middle Aged
• Skin Neoplasms (drug therapy, immunology)
• T-Lymphocytes, Regulatory (drug effects, immunology)