Ctla-4 blockade confers lymphocyte resistance to regulatory T-cells in advanced melanoma: surrogate marker of efficacy of tremelimumab?
OBJECTIVE
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.


METHODS
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).


CONCLUSIONS
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.
Ménard
Cédric
C
Center of Clinical Investigations, CBT507, Institut Gustave Roussy, Villejuif, France.
Ghiringhelli
François
F
Roux
Stephan
S
Chaput
Nathalie
N
Mateus
Christine
C
Grohmann
Ursula
U
Caillat-Zucman
Sophie
S
Zitvogel
Laurence
L
Robert
Caroline
C
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000187:drug effects* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000032:analysis; D060908:CTLA-4 Antigen; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology*; D008875:Middle Aged; D012878:Skin Neoplasms / Q000188:drug therapy / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000970:Antineoplastic Agents; D015415:Biomarkers; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C520704:tremelimumab