gp100(209-2M) peptide immunization of human lymphocyte antigen-A2+ stage I-III melanoma patients induces significant increase in antigen-specific effector and long-term memory CD8+ T cells.

Details

Serval ID
serval:BIB_BA46600F0D8F
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
gp100(209-2M) peptide immunization of human lymphocyte antigen-A2+ stage I-III melanoma patients induces significant increase in antigen-specific effector and long-term memory CD8+ T cells.
Journal
Clinical Cancer Research
Author(s)
Walker E.B., Haley D., Miller W., Floyd K., Wisner K.P., Sanjuan N., Maecker H., Romero P., Hu H.M., Alvord W.G., Smith J.W., Fox B.A., Urba W.J.
ISSN
1078-0432
Publication state
Published
Issued date
2004
Peer-reviewed
Oui
Volume
10
Number
2
Pages
668-680
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
Publication Status: ppublish
Abstract
Thirty-five HLA-A2(+) patients with completely resected stage I-III melanoma were vaccinated multiple times over 6 months with a modified melanoma peptide, gp100(209-2M), emulsified in Montanide adjuvant. Direct ex vivo gp100(209-2M) tetramer analysis of pre- and postvaccine peripheral blood mononuclear cells (PBMCs) demonstrated significant increases in the frequency of tetramer(+) CD8(+) T cells after immunization for 33 of 35 evaluable patients (median, 0.36%; range, 0.05-8.9%). Ex vivo IFN-gamma cytokine flow cytometry analysis of postvaccine PBMCs after brief gp100(209-2M) in vitro activation showed that for all of the patients studied tetramer(+) CD8(+) T cells produced IFN-gamma; however, some patients had significant numbers of tetramer(+) IFN-gamma(-) CD8(+)T cells suggesting functional anergy. Additionally, 8 day gp100(209-2M) in vitro stimulation (IVS) of pre- and postvaccine PBMCs resulted in significant expansion of tetramer(+) CD8(+) T cells from postvaccine cells for 34 patients, and these IVS tetramer(+) CD8(+) T cells were functionally responsive by IFN-gamma cytokine flow cytometry analysis after restimulation with either native or modified gp100 peptide. However, correlated functional and phenotype analysis of IVS-expanded postvaccine CD8(+) T cells demonstrated the proliferation of functionally anergic gp100(209-2M)- tetramer(+) CD8(+) T cells in several patients and also indicated interpatient variability of gp100(209-2M) stimulated T-cell proliferation. Flow cytometry analysis of cryopreserved postvaccine PBMCs from representative patients showed that the majority of tetramer(+) CD8+ T cells (78.1 +/- 4.2%) had either an "effector" (CD45 RA(+)/CCR7(-)) or an "effector-memory" phenotype (CD45RA(-)/CCR7(-)). Notably, analysis of PBMCs collected 12-24 months after vaccine therapy demonstrated the durable presence of gp100(209-2M)-specific memory CD8(+) T cells with high proliferation potential. Overall, this report demonstrates that after vaccination with a MHC class I-restricted melanoma peptide, resected nonmetastatic melanoma patients can mount a significant antigen-specific CD8(+) T-cell immune response with a functionally intact memory component. The data further support the combined use of tetramer binding and functional assays in correlated ex vivo and IVS settings as a standard for immunomonitoring of cancer vaccine patients.
Keywords
Antigens, Neoplasm, CD8-Positive T-Lymphocytes/immunology, CD8-Positive T-Lymphocytes/metabolism, Cancer Vaccines, Cell Line, Tumor, Cytokines/biosynthesis, Dendritic Cells/cytology, Dimerization, Flow Cytometry, HLA-A2 Antigen/metabolism, Humans, Immunologic Memory, Interferon-gamma/metabolism, Leukocytes, Mononuclear/metabolism, Melanoma/immunology, Melanoma/pathology, Membrane Glycoproteins/chemistry, Membrane Glycoproteins/immunology, Neoplasm Metastasis, Neoplasm Proteins/chemistry, Neoplasm Proteins/immunology, Neoplastic Cells, Circulating, Peptide Fragments/chemistry, Peptide Fragments/immunology, Peptides/chemistry, Phenotype, T-Lymphocytes/immunology
Pubmed
Web of science
Open Access
Yes
Create date
28/01/2008 11:28
Last modification date
20/08/2019 15:28
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