| CTLA-4 blockade increases antigen-specific CD8(+) T cells in prevaccinated patients with melanoma: three cases. | |
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MedLine Citation:
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PMID: 21465316 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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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:
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Title: Cancer immunology, immunotherapy : CII Volume: 60 ISSN: 1432-0851 ISO Abbreviation: Cancer Immunol. Immunother. Publication Date: 2011 Aug |
Date Detail:
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Created Date: 2011-07-22 Completed Date: 2011-10-04 Revised Date: 2013-05-24 |
Medline Journal Info:
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Nlm Unique ID: 8605732 Medline TA: Cancer Immunol Immunother Country: Germany |
Other Details:
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Languages: eng Pagination: 1137-46 Citation Subset: IM |
Affiliation:
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Immunology Program, Ludwig Center for Cancer Immunotherapy, Sloan-Kettering Institute, New York, NY 10065, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adult Aged 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 Female Humans Immunotherapy* Lymphocyte Activation / drug effects Male Melanoma / immunology, pathology, therapy* Middle Aged Neoplasm Metastasis Peptide Fragments / immunology Skin Neoplasms / immunology, pathology, therapy* Tumor Escape |
| Grant Support | |
ID/Acronym/Agency:
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K23 CA125205-05/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 |
| Chemical | |
Reg. No./Substance:
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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 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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