title: CTLA-4 blockade increases antigen-specific CD8(+) T cells in prevaccinated patients with melanoma: three cases.
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.
  
  
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Immunology Program, Ludwig Center for Cancer Immunotherapy, Sloan-Kettering Institute, New York, NY 10065, USA.
authors.forename: Jianda
authors.initials: J
authors.lastname: Yuan
authors.forename: Brian
authors.initials: B
authors.lastname: Ginsberg
authors.forename: David
authors.initials: D
authors.lastname: Page
authors.forename: Yanyun
authors.initials: Y
authors.lastname: Li
authors.forename: Teresa
authors.initials: T
authors.lastname: Rasalan
authors.forename: Humilidad F
authors.initials: HF
authors.lastname: Gallardo
authors.forename: Yinyan
authors.initials: Y
authors.lastname: Xu
authors.forename: Sylvia
authors.initials: S
authors.lastname: Adams
authors.forename: Nina
authors.initials: N
authors.lastname: Bhardwaj
authors.forename: Klaus
authors.initials: K
authors.lastname: Busam
authors.forename: Lloyd J
authors.initials: LJ
authors.lastname: Old
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
authors.forename: Achim
authors.initials: A
authors.lastname: Jungbluth
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D007167:Immunotherapy; D000074324:Ipilimumab; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010446:Peptide Fragments / Q000276:immunology; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D019139:Tumor Escape
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D019496:Cancer Vaccines; D016207:Cytokines; D000074324:Ipilimumab; D010446:Peptide Fragments