title: Tumor progression can occur despite the induction of very high levels of self/tumor antigen-specific CD8+ T cells in patients with melanoma.
abstract: The identification of many tumor-associated epitopes as nonmutated "self" Ags led to the hypothesis that the induction of large numbers of self/tumor Ag-specific T cells would be prevented because of central and peripheral tolerance. We report in this study on vaccination efforts in 95 HLA-A*0201 patients at high risk for recurrence of malignant melanoma who received prolonged immunization with the "anchor-modified" synthetic peptide, gp100209-217(210M). Vaccination using this altered peptide immunogen was highly effective at inducing large numbers of self/tumor-Ag reactive T cells in virtually every patient tested, with levels as high as 42% of all CD8+ T cells assessed by tetramer analysis. From 1 to 10% of all CD8+ cells were tumor-Ag reactive in 44% of patients and levels >10% were generated in 17% of patients. These studies were substantiated using the ELISPOT assay and a bulk cytokine release assay. Although our data regarding "tumor escape" were inconclusive, some patients had growing tumors that expressed Ag and HLA-A*0201 in the presence of high levels of antitumor T cells. There was no difference in the levels of antitumor Ag-specific T cells in patients who recurred compared with those that remained disease-free. Thus, the mere presence of profoundly expanded numbers of vaccine-induced, self/tumor Ag-specific T cells cannot by themselves be used as a "surrogate marker" for vaccine efficacy. Further, the induction of even high levels of antitumor T cells may be insufficient to alter tumor progression.
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. sar@nih.gov
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Richard M
authors.initials: RM
authors.lastname: Sherry
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Morton
authors.forename: William J
authors.initials: WJ
authors.lastname: Scharfman
authors.forename: James C
authors.initials: JC
authors.lastname: Yang
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Topalian
authors.forename: Richard E
authors.initials: RE
authors.lastname: Royal
authors.forename: Udai
authors.initials: U
authors.lastname: Kammula
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.forename: Marybeth S
authors.initials: MS
authors.lastname: Hughes
authors.forename: Douglas
authors.initials: D
authors.lastname: Schwartzentruber
authors.forename: David M
authors.initials: DM
authors.lastname: Berman
authors.forename: Susan L
authors.initials: SL
authors.lastname: Schwarz
authors.forename: Lien T
authors.initials: LT
authors.lastname: Ngo
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Mavroukakis
authors.forename: Donald E
authors.initials: DE
authors.lastname: White
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D007114:Immunization; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D008562:Membrane Glycoproteins / Q000276:immunology*; D008875:Middle Aged; D010446:Peptide Fragments / Q000276:immunology*; D012878:Skin Neoplasms / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D058951:gp100 Melanoma Antigen
chemical_list: D000951:Antigens, Neoplasm; D001324:Autoantigens; D019496:Cancer Vaccines; D008562:Membrane Glycoproteins; C548637:PMEL protein, human; D010446:Peptide Fragments; D058951:gp100 Melanoma Antigen