CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit

Blockade of inhibitory signals mediated by cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) has been shown to enhance T cell responses and induce durable clinical responses in patients with metastatic melanoma. The functional impact of anti-CTLA-4 therapy on human immune responses is still uncle...

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Published in:	Proceedings of the National Academy of Sciences - PNAS 2008-12, Vol.105 (51), p.20410-20415
Main Authors:	Yuan, Jianda, Gnjatic, Sacha, Li, Hao, Powel, Sarah, Gallardo, Humilidad F, Ritter, Erika, Ku, Geoffrey Y, Jungbluth, Achim A, Segal, Neil H, Rasalan, Teresa S, Manukian, Gregor, Xu, Yinyan, Roman, Ruth-Ann, Terzulli, Stephanie L, Heywood, Melanie, Pogoriler, Evelina, Ritter, Gerd, Old, Lloyd J, Allison, James P, Wolchok, Jedd D
Format:	Article
Language:	eng
Subjects:	Adult Aged Aged, 80 and over Antibodies Antibodies, Monoclonal - administration & dosage Antibodies, Monoclonal - pharmacology Antibodies, Monoclonal - therapeutic use Antigens Antigens, CD - immunology Antigens, Neoplasm - immunology B-Lymphocytes - immunology Biological Sciences Cancer Cells CTLA-4 Antigen Cytokines Cytokines - drug effects Dosage Humans Immunity - drug effects Immunotherapy Immunotherapy - methods Ipilimumab Lymphocytes Melanoma Melanoma - drug therapy Melanoma - pathology Membrane Proteins - immunology Middle Aged Monoclonal antibodies Neoplasm Metastasis Proteins T lymphocytes T-Cell Antigen Receptor Specificity T-Lymphocytes - drug effects T-Lymphocytes - immunology Treatment Outcome Tumors Vaccination
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Summary:	Blockade of inhibitory signals mediated by cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) has been shown to enhance T cell responses and induce durable clinical responses in patients with metastatic melanoma. The functional impact of anti-CTLA-4 therapy on human immune responses is still unclear. To explore this, we analyzed immune-related adverse events and immune responses in metastatic melanoma patients treated with ipilimumab, a fully human anti-CTLA-4 monoclonal antibody. Fifteen patients were selected on the basis of availability of suitable specimens for immunologic monitoring, and eight of these showed evidence of clinical benefit. Five of the eight patients with evidence of clinical benefit had NY-ESO-1 antibody, whereas none of seven clinical non-responders was seropositive for NY-ESO-1. All five NY-ESO-1 seropositive patients had clearly detectable CD4⁺ and CD8⁺ T cells against NY-ESO-1 following treatment with ipilimumab. One NY-ESO-1 seronegative clinical responder also had a NY-ESO-1 CD4⁺ and CD8⁺ T cell response, possibly related to prior vaccination with NY-ESO-1. Among five clinical non-responders analyzed, only one had a NY-ESO-1 CD4⁺ T cell response and this patient did not have detectable anti-NY-ESO-1 antibody. Overall, NY-ESO-1-specific T cell responses increased in frequency and functionality during anti-CTLA-4 treatment, revealing a polyfunctional response pattern of IFN-γ, MIP-1β and TNF-α. We therefore suggest that CTLA-4 blockade enhanced NY-ESO-1 antigen-specific B cell and T cell immune responses in patients with durable objective clinical responses and stable disease. These data provide an immunologic rationale for the efficacy of anti-CTLA-4 therapy and call for immunotherapeutic designs that combine NY-ESO-1 vaccination with CTLA-4 blockade.
ISSN:	0027-8424 1091-6490