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


Authors: Yuan, J.; Gnjatic, S.; Li, H.; Powel, S.; Gallardo, H. F.; Ritter, E.; Ku, G. Y.; Jungbluth, A. A.; Segal, N. H.; Rasalan, T. S.; Manukian, G.; Xu, Y.; Roman, R. A.; Terzulli, S. L.; Heywood, M.; Pogoriler, E.; Ritter, G.; Old, L. J.; Allison, J. P.; Wolchok, J. D.
Article Title: CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit
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+ 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. © 2008 by The National Academy of Sciences of the USA.
Keywords: controlled study; treatment outcome; human cell; clinical trial; unspecified side effect; cancer patient; temozolomide; cd8+ t lymphocyte; t-lymphocytes; alpha2b interferon; dendritic cell vaccine; ipilimumab; melanoma; controlled clinical trial; phase 2 clinical trial; randomized controlled trial; macrophage inflammatory protein 1beta; membrane proteins; b-lymphocytes; cytokines; antibodies, monoclonal; tumor necrosis factor alpha; immunotherapy; antigens, neoplasm; gamma interferon; ny eso 1 antigen; cd4+ t lymphocyte; t-cell antigen receptor specificity; vaccination; neoplasm metastasis; immunity; antigens, cd; cytotoxic t lymphocyte antigen 4; cytotoxic t lymphocyte-associated antigen 4; tumor therapy
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 105
Issue: 51
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2008-12-23
Start Page: 20410
End Page: 20415
Language: English
DOI: 10.1073/pnas.0810114105
PUBMED: 19074257
PROVIDER: scopus
PMCID: PMC2629307
DOI/URL:
Notes: --- - "Cited By (since 1996): 74" - "Export Date: 17 November 2011" - "CODEN: PNASA" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Jedd D Wolchok
    669 Wolchok
  2. Neil Howard Segal
    107 Segal
  3. Hao Li
    7 Li
  4. Geoffrey Yuyat Ku
    92 Ku
  5. Ruth-Ann Roman
    30 Roman
  6. James P Allison
    129 Allison
  7. Sacha Gnjatic
    111 Gnjatic
  8. Achim Jungbluth
    341 Jungbluth
  9. Gerd Ritter
    158 Ritter
  10. Erika Ritter
    34 Ritter
  11. Jianda Yuan
    100 Yuan
  12. Lloyd J Old
    386 Old
  13. Teresa Rasalan
    25 Rasalan
  14. Yinyan Xu
    11 Xu
  15. Sarah Powel
    5 Powel