title: Time-dependent cytotoxic drugs selectively cooperate with IL-18 for cancer chemo-immunotherapy.
abstract: BACKGROUND
  Time-dependent chemotherapeutic agents can selectively target tumor cells in susceptible phases of the cell cycle however a fraction of tumor cells in non-vulnerable cell cycle phases remain drug-resistant. Immunotherapy represents a promising approach to overcome the limitation of phase-specific drugs and improve their clinical efficacy. Here, we investigated the potential use of anticancer chemotherapeutic drugs in combination with IL-18, a cytokine with strong immunostimulatory properties.
  
  
  METHODS
  Four chemotherapeutic drugs commonly used in ovarian cancer were first tested for the ability to increase the immunogenicity and killing of the murine ovarian cancer cell line ID8 in vitro. Chemotherapeutric agents with measured time-dependent immune-enhancing effects were then tested for antitumor effectiveness in vivo in combination with IL-18 immunotherapy using the ID8-Vegf ovarian cancer model.
  
  
  RESULTS
  Paclitaxel or topotecan exposure alone mediated incomplete, time-dependent killing against the murine ovarian cancer cell line ID8 in vitro, whereas carboplatin or gemcitabine mediated comprehensive, dose-dependent killing. In the plateau phase of the time-dependent killing by topotecan or paclitaxel, drug-resistant ID8 cells were more immunogenic with elevated expression of MHC-I and Fas, and increased sensitivity to CTL and Fas agonistic antibody in vitro. Moreover, the antitumor effectiveness of time-dependent agents in vivo was significantly improved with the addition of IL-18 through a T cell-dependent mechanism, while the effectiveness of drugs without significant phase specificity were not.
  
  
  CONCLUSIONS
  Tumor immunotherapy with IL-18 can significantly augment the killing fraction of phase-specific chemotherapeutic drugs and provide survival benefit. The safety profile of IL-18 and its positive interactions with select anticancer chemotherapeutic agents strongly supports the clinical investigation of this combinatorial approach.
authors: Ovarian Cancer Research Center, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Ioannis.Alagkiozidis@uth.tmc.edu
authors: Ioannis
authors: I
authors: Alagkiozidis
authors: Andrea
authors: A
authors: Facciabene
authors: Marinos
authors: M
authors: Tsiatas
authors: Carmine
authors: C
authors: Carpenito
authors: Fabian
authors: F
authors: Benencia
authors: Sarah
authors: S
authors: Adams
authors: Zdenka
authors: Z
authors: Jonak
authors: Carl H
authors: CH
authors: June
authors: Daniel J
authors: DJ
authors: Powell
authors: George
authors: G
authors: Coukos
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