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CTLA-4 blockade increases antigen-specific CD8(+) T cells in prevaccinated patients with melanoma: three cases.
- Source :
-
Cancer immunology, immunotherapy : CII [Cancer Immunol Immunother] 2011 Aug; Vol. 60 (8), pp. 1137-46. Date of Electronic Publication: 2011 Apr 05. - Publication Year :
- 2011
-
Abstract
- 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.<br />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.<br />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.<br />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.
- Subjects :
- Adult
Aged
Antibodies, Monoclonal pharmacology
Antigens, CD metabolism
Antigens, Neoplasm immunology
CD8-Positive T-Lymphocytes immunology
CD8-Positive T-Lymphocytes metabolism
CD8-Positive T-Lymphocytes pathology
CTLA-4 Antigen
Cells, Cultured
Cytokines metabolism
Female
Humans
Ipilimumab
Lymphocyte Activation drug effects
Male
Melanoma immunology
Melanoma pathology
Middle Aged
Neoplasm Metastasis
Peptide Fragments immunology
Skin Neoplasms immunology
Skin Neoplasms pathology
Tumor Escape
Antibodies, Monoclonal administration & dosage
CD8-Positive T-Lymphocytes drug effects
Cancer Vaccines
Immunotherapy
Melanoma therapy
Skin Neoplasms therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0851
- Volume :
- 60
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Cancer immunology, immunotherapy : CII
- Publication Type :
- Academic Journal
- Accession number :
- 21465316
- Full Text :
- https://doi.org/10.1007/s00262-011-1011-9