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CTLA-4 blockade enhances polyfunctional NY-ES0-1 specific T cell responses in metastatic melanoma patients with clinical benefit
- Source :
- Proceedings of the National Academy of Sciences of the United States. Dec 23, 2008, Vol. 105 Issue 51, p20410, 6 p.
- Publication Year :
- 2008
-
Abstract
- 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.sup.+] and [CD8.sup.+] T cells against NY-ESO-1 following treatment with ipilimumab. One NYESO-1 seronegative clinical responder also had a NY-ESO-1 [CD4.sup.+] and [CD8.sup.+] 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.sup.+] T cell response and this patient did not have detectable anti-NY-ESO-1 antibody. Overall, NY-ESO-l-specific T cell responses increased in frequency and functionality during anti-CTLA-4 treatment, revealing a polyfunctional response pattern of IFN-[gamma], MIP-1[beta] and TNF-[alpha]. 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. Cytotoxic | lymphocyte-associated antigen 4 | immunotherapy | tumor therapy
- Subjects :
- Immune response -- Health aspects
Immunotherapy -- Health aspects
Immunotherapy -- Research
Antigen receptors, T cell -- Physiological aspects
Antigen receptors, T cell -- Health aspects
T cells -- Receptors
T cells -- Physiological aspects
T cells -- Health aspects
Science and technology
Subjects
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 105
- Issue :
- 51
- Database :
- Gale General OneFile
- Journal :
- Proceedings of the National Academy of Sciences of the United States
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.191817466