Evaluation of peptide vaccine immunogenicity in draining lymph nodes and peripheral blood of melanoma patients.
Many peptide epitopes for cytotoxic T lymphocytes (CTLs) have been identified from melanocytic differentiation proteins. Vaccine trials with these peptides have been limited mostly to those associated with HLA-A2, and immune responses have been detected inconsistently. Cases of clinical regression have been observed after peptide vaccination in some trials, but melanoma regressions have not correlated well with T-cell responses measured in peripheral blood lymphocytes (PBLs). We vaccinated stage IV melanoma patients with a mixture of gp100 and tyrosinase peptides restricted by HLA-A1 (DAEKSDICTDEY), HLA-A2 (YLEPGPVTA and YMDGTMSQV) and HLA-A3 (ALLAVGATK) in an emulsion with GM-CSF and Montanide ISA-51 adjuvant. CTL responses were assessed in PBLs and in a lymph node draining a vaccine site (sentinel immunized node, SIN). We found CTL responses to vaccinating peptides in the SIN in 5/5 patients (100%). Equivalent assays detected peptide-reactive CTLs in PBLs of 2 of these 5 patients (40%). CTLs expanded from the SIN lysed melanoma cells naturally expressing tyrosinase or gp100. We demonstrated immunogenicity for peptides restricted by HLA-A1 and -A3 and for 1 HLA-A2 restricted peptide, YMDGTMSQV. Immune monitoring of clinical trials by evaluation of PBLs alone may under-estimate immunogenicity; evaluation of SIN provides a new and sensitive approach for defining responses to tumor vaccines and correlating these responses with clinical outcomes. This combination of an immunogenic vaccine strategy with a sensitive analysis of CTL responses demonstrates the potential for inducing and detecting anti-tumor immune responses in the majority of melanoma patients.
Yamshchikov
G V
GV
Division of Surgical Oncology, Department of Surgery, University of Virginia HSC, Charlottesville, VA 22908, USA.
Barnd
D L
DL
Eastham
S
S
Galavotti
H
H
Patterson
J W
JW
Deacon
D H
DH
Teates
D
D
Neese
P
P
Grosh
W W
WW
Petroni
G
G
Engelhard
V H
VH
Slingluff
C L
CL
D000328:Adult; D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines / Q000276:immunology*; D015234:HLA-A Antigens / Q000276:immunology*; D006801:Humans; D008198:Lymph Nodes / Q000276:immunology*; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D058950:Melanoma-Specific Antigens; D008562:Membrane Glycoproteins / Q000276:immunology*; D008875:Middle Aged; D008969:Molecular Sequence Data; D014442:Monophenol Monooxygenase / Q000276:immunology*; D009363:Neoplasm Proteins / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D058951:gp100 Melanoma Antigen
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D015234:HLA-A Antigens; D058950:Melanoma-Specific Antigens; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C548637:PMEL protein, human; D010446:Peptide Fragments; D058951:gp100 Melanoma Antigen; D014442:Monophenol Monooxygenase