title: Amplification of virus-induced antimelanoma T-cell reactivity by high-dose interferon-alpha2b: implications for cancer vaccines.
abstract: OBJECTIVE
  The therapeutic effectiveness of cancer vaccines, composed of tumor antigens that are also self-antigens, may be limited by the normal mechanisms that preserve immunological tolerance. Consistent with this notion, we found that vaccination of melanoma patients with recombinant viral vaccines expressing gp100 (a melanoma antigen also expressed by normal melanocytes) produced only transient increases in noncytotoxic T cells specific for immunodominant gp100 epitopes. To improve the therapeutic effects of these vaccines, IFN-alpha2b (IFN-alpha) was administered to some high-risk patients.
  
  
  METHODS
  7 HLA-A*0201(+) patients were injected with high doses of IFN-alpha (20 MU/m(2) x 20 doses) at various times after completing the vaccination protocol. Clinical toxicity and responses were documented, and the effects on gp100-reactive T cells were measured by IFN-gamma enzyme-linked immunospot assays, tetramers of HLA-A*0201 and gp100 epitopes, and cellular cytotoxicity assays.
  
  
  RESULTS
  In patients who had previously responded to vaccination, high doses of IFN-alpha recalled gp100-reactive T cells with the ability to kill gp100-expressing tumor targets in vitro. Concomitant with the reappearance of these cytotoxic T cells, tumor regression was observed in the two patients with clinically evident metastatic disease.
  
  
  CONCLUSIONS
  The finding that high-dose IFN recalls previously activated tumor-reactive T cells with potent killing ability suggests a strategy to maintain antitumor responses initiated by cancer vaccines.
authors.affiliation: Division of Molecular and Cellular Biology, Research Institute, Sunnybrook and Women's College Health Sciences Center, Toronto, Ontario, Canada.
authors.forename: Igor
authors.initials: I
authors.lastname: Astsaturov
authors.forename: Teresa
authors.initials: T
authors.lastname: Petrella
authors.forename: E Umit
authors.initials: EU
authors.lastname: Bagriacik
authors.forename: Mark
authors.initials: M
authors.lastname: de Benedette
authors.forename: Robert
authors.initials: R
authors.lastname: Uger
authors.forename: Gail
authors.initials: G
authors.lastname: Lumber
authors.forename: Neil
authors.initials: N
authors.lastname: Berinstein
authors.forename: Ileana
authors.initials: I
authors.lastname: Elias
authors.forename: Neill
authors.initials: N
authors.lastname: Iscoe
authors.forename: Caitlin
authors.initials: C
authors.lastname: Hammond
authors.forename: Paul
authors.initials: P
authors.lastname: Hamilton
authors.forename: David E
authors.initials: DE
authors.lastname: Spaner
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D028121:Canarypox virus / Q000502:physiology*; D019496:Cancer Vaccines / Q000008:administration & dosage*; D002455:Cell Division; D003602:Cytotoxicity, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015234:HLA-A Antigens / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage*; D008207:Lymphatic Metastasis; D008297:Male; D008544:Melanocytes / Q000276:immunology / Q000473:pathology; D008545:Melanoma / Q000276:immunology* / Q000556:secondary / Q000628:therapy; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D011994:Recombinant Proteins; D013601:T-Lymphocytes / Q000276:immunology*; D014611:Vaccination; D058951:gp100 Melanoma Antigen
chemical_list: D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C548637:PMEL protein, human; D011994:Recombinant Proteins; D058951:gp100 Melanoma Antigen