title: Immunotherapy of neuroblastoma by an Interleukin-21-secreting cell vaccine involves survivin as antigen.
abstract: OBJECTIVE
  IL-21 is the most recently identified member of the IL-2 cytokine family. Here we studied the therapeutic efficacy of IL-21-gene-modified cells (Neuro2a/IL-21) in a syngeneic metastatic neuroblastoma (NB) model.
  
  
  METHODS
  Neuro2a/IL-21 cells were tested as subcutaneous (sc) vaccine both in prophylactic and therapeutic settings. Depletion studies, cytotoxicity assay and immunohistochemical analyses were carried out to evaluate the mechanisms involved in tumor rejection.
  
  
  RESULTS
  When injected sc in syngeneic A/J mice viable Neuro2a/IL-21 cells were rejected and induced resistance to a subsequent iv challenge with Neuro2a parental cells (Neuro2a/pc), suggesting the involvement of an immune response. More importantly, in mice bearing Neuro2a/pc micrometastases, a single sc injection of Neuro2a/IL-21 cells significantly increased the mean tumor-free survival of treated animals (43 vs. 22 days) and cured 14% of them. The administration of two or three doses of Neuro2a/IL-21 cell vaccine further increased the mean survival time to 54 and 75 days, and the cure rate to 27 and 33%, respectively, whereas the use of unmodified Neuro2a or mock-transfected cells had no effect. In vivo cell subset depletion and a Winn-assay indicated the involvement of CD8 + CTLs. Immunohistochemical analysis indicated a reduction of CD31+ and VEGFR2+ microvessels in late metastases from therapeutically vaccinated mice. A role of survivin as antigen was suggested by in vitro assays using survivin-synthetic CTL-epitopes.
  
  
  CONCLUSIONS
  Our present data indicate that IL-21-secreting NB cells are effective as therapeutic vaccine in mice bearing metastatic NB, through a specific CTL response involving survivin as antigen, and suggest a potential interest for IL-21 in NB immuno-gene therapy.
authors.affiliation: Laboratory of Immunological Therapy, Istituto Nazionale per la Ricerca sul Cancro, Largo Benzi 10, 16132 Genoa, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Croce
authors.forename: Raffaella
authors.initials: R
authors.lastname: Meazza
authors.forename: Anna M
authors.initials: AM
authors.lastname: Orengo
authors.forename: Marina
authors.initials: M
authors.lastname: Fabbi
authors.forename: Martina
authors.initials: M
authors.lastname: Borghi
authors.forename: Domenico
authors.initials: D
authors.lastname: Ribatti
authors.forename: Beatrice
authors.initials: B
authors.lastname: Nico
authors.forename: Barbara
authors.initials: B
authors.lastname: Carlini
authors.forename: Vito
authors.initials: V
authors.lastname: Pistoia
authors.forename: Maria Valeria
authors.initials: MV
authors.lastname: Corrias
authors.forename: Silvano
authors.initials: S
authors.lastname: Ferrini
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019496:Cancer Vaccines / Q000627:therapeutic use*; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D007167:Immunotherapy; D051034:Inhibitor of Apoptosis Proteins; D007371:Interferon-gamma / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D051379:Mice; D008805:Mice, Inbred A; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008869:Microtubule-Associated Proteins / Q000276:immunology / Q000378:metabolism*; D009447:Neuroblastoma / Q000276:immunology / Q000628:therapy*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D000077022:Survivin; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection; D014407:Tumor Cells, Cultured; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014611:Vaccination; D000098546:Interleukin-21
chemical_list: C117749:Birc5 protein, mouse; D019496:Cancer Vaccines; D051034:Inhibitor of Apoptosis Proteins; D007378:Interleukins; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D000077022:Survivin; D007371:Interferon-gamma; D014446:Tyrosine 3-Monooxygenase; D000098546:Interleukin-21