title: Increased vaccine-specific T cell frequency after peptide-based vaccination correlates with increased susceptibility to in vitro stimulation but does not lead to tumor regression.
abstract: Although in vitro sensitization assays have shown increased melanoma Ag (MA)-specific CTL reactivity after vaccination with MA peptides, clinical responses have been uncommon. This paradox questions whether data obtained from the in vitro stimulation and expansion of T cells lead to an overestimation of the immune response to vaccines. Using HLA/peptide tetramer (tHLA), we enumerated MA-specific T cell precursor frequency (TCPF) directly in PBMC from 23 melanoma patients vaccinated with gp100:209-217(210M) (g209-2M) peptide. Vaccine-specific TCPF was higher in postvaccination PBMC from seven of seven patients treated with peptide alone and four of five patients treated with peptide plus IL-12 (range of postvaccination TCPF, 0.2-2.4% and 0.2-2.5%, respectively). The increased TCPF correlated with enhanced susceptibility to in vitro stimulation with the relevant epitope. Paradoxically, no increase in postvaccination TCPF was observed in most patients who had been concomitantly treated with IL-2 (1 of 11 patients; range of postvaccination TCPF, 0.02-1.0%), a combination associated with enhanced rates of tumor regression. The lack of increase in TCPF seen in these patients corresponded to inability to elicit expansion of vaccine-specific T cells in culture. This study shows that a peptide-based vaccine can effectively generate a quantifiable T cell-specific immune response in the PBMC of cancer patients, though such a response does not associate with a clinically evident regression of metastatic melanoma.
authors.affiliation: Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: K H
authors.initials: KH
authors.lastname: Lee
authors.forename: E
authors.initials: E
authors.lastname: Wang
authors.forename: M B
authors.initials: MB
authors.lastname: Nielsen
authors.forename: J
authors.initials: J
authors.lastname: Wunderlich
authors.forename: S
authors.initials: S
authors.lastname: Migueles
authors.forename: M
authors.initials: M
authors.lastname: Connors
authors.forename: S M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: S A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: F M
authors.initials: FM
authors.lastname: Marincola
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D004359:Drug Therapy, Combination; D006801:Humans; D007111:Immunity, Cellular; D007376:Interleukin-2 / Q000494:pharmacology; D008545:Melanoma / Q000276:immunology* / Q000556:secondary; D008562:Membrane Glycoproteins / Q000276:immunology*; D009363:Neoplasm Proteins / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology*; D010455:Peptides; D013601:T-Lymphocytes / Q000276:immunology*; D014611:Vaccination; D058951:gp100 Melanoma Antigen
chemical_list: D019496:Cancer Vaccines; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C548637:PMEL protein, human; D010446:Peptide Fragments; D010455:Peptides; C548638:g209-2M melanoma peptide; D058951:gp100 Melanoma Antigen