title: Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with {alpha}-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma.
abstract: OBJECTIVE
  A phase I/II trial was performed to evaluate the safety and immunogenicity of a novel vaccination with α-type 1 polarized dendritic cells (αDC1) loaded with synthetic peptides for glioma-associated antigen (GAA) epitopes and administration of polyinosinic-polycytidylic acid [poly(I:C)] stabilized by lysine and carboxymethylcellulose (poly-ICLC) in HLA-A2(+) patients with recurrent malignant gliomas. GAAs for these peptides are EphA2, interleukin (IL)-13 receptor-α2, YKL-40, and gp100.
  
  
  METHODS
  Twenty-two patients (13 with glioblastoma multiforme [GBM], five with anaplastic astrocytoma [AA], three with anaplastic oligodendroglioma [AO], and one with anaplastic oligoastrocytoma [AOA]) received at least one vaccination, and 19 patients received at least four vaccinations at two αDC1 dose levels (1 × or 3 × 10(7)/dose) at 2-week intervals intranodally. Patients also received twice weekly intramuscular injections of 20 μg/kg poly-ICLC. Patients who demonstrated positive radiologic response or stable disease without major adverse events were allowed to receive booster vaccines. T-lymphocyte responses against GAA epitopes were assessed by enzyme-linked immunosorbent spot and HLA-tetramer assays.
  
  
  RESULTS
  The regimen was well-tolerated. The first four vaccines induced positive immune responses against at least one of the vaccination-targeted GAAs in peripheral blood mononuclear cells in 58% of patients. Peripheral blood samples demonstrated significant upregulation of type 1 cytokines and chemokines, including interferon-α and CXCL10. Nine (four GBM, two AA, two AO, and one AOA) achieved progression-free status lasting at least 12 months. One patient with recurrent GBM demonstrated sustained complete response. IL-12 production levels by αDC1 positively correlated with time to progression.
  
  
  CONCLUSIONS
  These data support safety, immunogenicity, and preliminary clinical activity of poly-ICLC-boosted αDC1-based vaccines.
authors.affiliation: G12.a Research Pavilion at the Hillman Cancer Center, 5117 Centre Ave, Pittsburgh, PA 15213-1863, USA. okadah@upmc.edu
authors.forename: Hideho
authors.initials: H
authors.lastname: Okada
authors.forename: Pawel
authors.initials: P
authors.lastname: Kalinski
authors.forename: Ryo
authors.initials: R
authors.lastname: Ueda
authors.forename: Aki
authors.initials: A
authors.lastname: Hoji
authors.forename: Gary
authors.initials: G
authors.lastname: Kohanbash
authors.forename: Teresa E
authors.initials: TE
authors.lastname: Donegan
authors.forename: Arlan H
authors.initials: AH
authors.lastname: Mintz
authors.forename: Johnathan A
authors.initials: JA
authors.lastname: Engh
authors.forename: David L
authors.initials: DL
authors.lastname: Bartlett
authors.forename: Charles K
authors.initials: CK
authors.lastname: Brown
authors.forename: Herbert
authors.initials: H
authors.lastname: Zeh
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Holtzman
authors.forename: Todd A
authors.initials: TA
authors.lastname: Reinhart
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Whiteside
authors.forename: Lisa H
authors.initials: LH
authors.lastname: Butterfield
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Hamilton
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Potter
authors.forename: Ian F
authors.initials: IF
authors.lastname: Pollack
authors.forename: Andres M
authors.initials: AM
authors.lastname: Salazar
authors.forename: Frank S
authors.initials: FS
authors.lastname: Lieberman
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D002266:Carboxymethylcellulose Sodium / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016764:Cell Polarity / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D000939:Epitopes; D005260:Female; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D007369:Interferon Inducers / Q000627:therapeutic use*; D018664:Interleukin-12 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015166:Monitoring, Immunologic; D011070:Poly I-C / Q000627:therapeutic use*; D011107:Polylysine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016016:Proportional Hazards Models; D012008:Recurrence; D022223:Vaccines, Subunit / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D000939:Epitopes; D007369:Interferon Inducers; D022223:Vaccines, Subunit; D018664:Interleukin-12; D011107:Polylysine; C019531:poly ICLC; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C