title: Synergistic enhancement of cellular immune responses by the novel Toll receptor 7/8 agonist 3M-007 and interferon-γ: implications for therapy of cutaneous T-cell lymphoma.
abstract: Cutaneous T-cell lymphoma (CTCL) is responsive at all stages to immunotherapy. We determined whether a novel agonist for Toll-like receptor (TLR) 7/8 (3M-007) combined with either interferon-γ (IFN-γ) or interleukin-15 (IL-15) would enhance patients' immune responses in vitro. Our data demonstrate that IFN-γ or IL-15 in combination with 007 significantly increases patients' natural killer (NK) cytolytic activity against CTCL tumor cell lines and synergistically induces dendritic cell cytokines, compared to 007 alone. Microarray studies of gene expression of patients' peripheral blood mononuclear cells (PBMCs) primed with IFN-γ followed by stimulation with 007 identified significant up-regulation of the expression of IL-12 p35 (α-chain), IL-12 p40 (β-chain), and nine IFN-α genes. Importantly, the underlying mechanism of increased levels of IFN-α and IL-12 from combined treatment appears to involve IFN regulatory factor 8 (IRF-8). These results further support our hypothesis that combinations of biological modifiers activating different arms of the immune system may provide significant therapeutic benefits for patients with advanced CTCL.
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, PA 19104, USA. mwysocka@mail.med.upenn.edu
authors.forename: Maria
authors.initials: M
authors.lastname: Wysocka
authors.forename: Noor
authors.initials: N
authors.lastname: Dawany
authors.forename: Bernice
authors.initials: B
authors.lastname: Benoit
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Kossenkov
authors.forename: Andrea B
authors.initials: AB
authors.lastname: Troxel
authors.forename: Joel M
authors.initials: JM
authors.lastname: Gelfand
authors.forename: Michael Kelly
authors.initials: MK
authors.lastname: Sell
authors.forename: Louise C
authors.initials: LC
authors.lastname: Showe
authors.forename: Alain H
authors.initials: AH
authors.lastname: Rook
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004357:Drug Synergism; D020869:Gene Expression Profiling; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects*; D007167:Immunotherapy / Q000379:methods; D016898:Interferon-alpha / Q000096:biosynthesis; D007371:Interferon-gamma / Q000494:pharmacology* / Q000627:therapeutic use; D018664:Interleukin-12 / Q000096:biosynthesis; D019409:Interleukin-15 / Q000494:pharmacology / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D016410:Lymphoma, T-Cell, Cutaneous / Q000188:drug therapy*; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D051200:Toll-Like Receptor 8 / Q000819:agonists*
chemical_list: D016898:Interferon-alpha; D019409:Interleukin-15; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D018664:Interleukin-12; D007371:Interferon-gamma