title: IRX-2, a novel immunotherapeutic, enhances functions of human dendritic cells.
abstract: BACKGROUND
  In a recent phase II clinical trial for HNSCC patients, IRX-2, a cell-derived biologic, promoted T-cell infiltration into the tumor and prolonged overall survival. Mechanisms responsible for these IRX-2-mediated effects are unknown. We hypothesized that IRX-2 enhanced tumor antigen-(TA)-specific immunity by up-regulating functions of dendritic cells (DC).
  
  
  RESULTS
  Monocyte-derived DC obtained from 18 HNSCC patients and 12 healthy donors were matured using IRX-2 or a mix of TNF-α, IL-1β and IL-6 ("conv. mix"). Multicolor flow cytometry was used to study the DC phenotype and antigen processing machinery (APM) component expression. ELISPOT and cytotoxicity assays were used to evaluate tumor-reactive cytotoxic T lymphocytes (CTL). IL-12p70 and IL-10 production by DC was measured by Luminex® and DC migration toward CCL21 was tested in transwell migration assays. IRX-2-matured DC functions were compared with those of conv. mix-matured DC. IRX-2-matured DC expressed higher levels (p<0.05) of CD11c, CD40, CCR7 as well as LMP2, TAP1, TAP2 and tapasin than conv. mix-matured DC. IRX-2-matured DC migrated significantly better towards CCL21, produced more IL-12p70 and had a higher IL12p70/IL-10 ratio than conv. mix-matured DC (p<0.05 for all). IRX-2-matured DC carried a higher density of tumor antigen-derived peptides, and CTL primed with these DC mediated higher cytotoxicity against tumor targets (p<0.05) compared to the conv. mix-matured DC.
  
  
  CONCLUSIONS
  Excellent ability of IRX-2 to induce ex vivo DC maturation in HNSCC patients explains, in part, its clinical benefits and emphasizes its utility in ex vivo maturation of DC generated for therapy.
authors: University of Pittsburgh, Department of Pathology and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
authors: Bastian
authors: B
authors: Schilling
authors: Malgorzata
authors: M
authors: Harasymczuk
authors: Patrick
authors: P
authors: Schuler
authors: James
authors: J
authors: Egan
authors: Soldano
authors: S
authors: Ferrone
authors: Theresa L
authors: TL
authors: Whiteside
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000628:therapy; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D016207:Cytokines / Q000008:administration & dosage / Q000494:pharmacology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006258:Head and Neck Neoplasms / Q000628:therapy; D006801:Humans; D016130:Immunophenotyping; D007167:Immunotherapy; D010587:Phagocytosis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D016207:Cytokines; C114857:IRX 2