Document Detail

CTLA-4 blockade increases antigen-specific CD8(+) T cells in prevaccinated patients with melanoma: three cases.
MedLine Citation:
PMID:  21465316     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibodies, such as ipilimumab, have generated measurable immune responses to Melan-A, NY-ESO-1, and gp100 antigens in metastatic melanoma. Vaccination against such targets has potential for immunogenicity and may produce an effector-memory T-cell response.
METHODS: To determine the effect of CTLA-4 blockade on antigen-specific responses following vaccination, in-depth immune monitoring was performed on three ipilimumab-treated patients prevaccinated with gp100 DNA (IMF-24), gp100(209-217) and tyrosinase peptides plus GM-CSF DNA (IMF-32), or NY-ESO-1 protein plus imiquimod (IMF-11); peripheral blood mononuclear cells were analyzed by tetramer and/or intracellular cytokine staining following 10-day culture with HLA-A*0201-restricted gp100(209-217) (ITDQVPFSV), tyrosinase(369-377) (YMDGTMSQV), or 20-mer NY-ESO-1 overlapping peptides, respectively. Tumors from IMF-32 were analyzed by immunohistochemistry to help elucidate mechanism(s) underlying tumor escape.
RESULTS: Following vaccination, patients generated weak to no CD4(+) or CD8(+) T-cell response specific to the vaccine antigen but demonstrated increases in effector-memory (CCR7(lo)CD45RA(lo)) tetramer(+)CD8(+) T cells. After ipilimumab induction, patients experienced a robust, although sometimes transient, antigen-specific response for gp100 (IMF-32 and IMF-24) or NY-ESO-1 (IMF-11) and produced polyfunctional intracellular cytokines. Primary and metastatic tumors expressed tyrosinase but not gp100 or class I/II MHC molecules.
CONCLUSION: Vaccination induced a measurable antigen-specific T-cell response that increased following CTLA-4 blockade, potentially "boosting" the vaccine-primed response. Tumor escape may be related to antigen loss or lack of MHC expression necessary for immune activity. These results in a limited number of patients support the need for further research into combining vaccination with ipilimumab and provide insight into mechanisms underlying tumor escape.
Jianda Yuan; Brian Ginsberg; David Page; Yanyun Li; Teresa Rasalan; Humilidad F Gallardo; Yinyan Xu; Sylvia Adams; Nina Bhardwaj; Klaus Busam; Lloyd J Old; James P Allison; Achim Jungbluth; Jedd D Wolchok
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Publication Detail:
Type:  Case Reports; Clinical Trial; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Review     Date:  2011-04-05
Journal Detail:
Title:  Cancer immunology, immunotherapy : CII     Volume:  60     ISSN:  1432-0851     ISO Abbreviation:  Cancer Immunol. Immunother.     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-07-22     Completed Date:  2011-10-04     Revised Date:  2014-07-04    
Medline Journal Info:
Nlm Unique ID:  8605732     Medline TA:  Cancer Immunol Immunother     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  1137-46     Citation Subset:  IM    
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MeSH Terms
Antibodies, Monoclonal / administration & dosage*,  pharmacology
Antigens, CD / metabolism
Antigens, Neoplasm / immunology
CD8-Positive T-Lymphocytes / drug effects*,  immunology,  metabolism,  pathology
CTLA-4 Antigen
Cancer Vaccines*
Cells, Cultured
Cytokines / metabolism
Lymphocyte Activation / drug effects
Melanoma / immunology,  pathology,  therapy*
Middle Aged
Neoplasm Metastasis
Peptide Fragments / immunology
Skin Neoplasms / immunology,  pathology,  therapy*
Tumor Escape
Grant Support
K23 CA125205-05/CA/NCI NIH HHS; P30 CA008748/CA/NCI NIH HHS; P50 AT002779/AT/NCCAM NIH HHS; P50AT002779/AT/NCCAM NIH HHS; R01 CA056821/CA/NCI NIH HHS; RC2 CA148468/CA/NCI NIH HHS
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Antigens, CD; 0/Antigens, Neoplasm; 0/CTLA-4 Antigen; 0/CTLA4 protein, human; 0/Cancer Vaccines; 0/Cytokines; 0/Peptide Fragments; 0/ipilimumab

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