Time-dependent cytotoxic drugs selectively cooperate with IL-18 for cancer chemo-immunotherapy

Journal of Translational Medicine

Research

Fabian Benencia¹  Carl H June¹  Carmine Carpenito¹  Zdenka Jonak²  Ioannis Alagkiozidis³  Andrea Facciabene³  Marinos Tsiatas³  Sarah Adams³  George Coukos⁴  Daniel J Powell⁵ 

[1] Abramson Family Cancer Research Institute, School of Medicine, University of Pennsylvania, Philadelphia, USA;GlaxoSmithKline, King of Prussia, USA;Ovarian Cancer Research Center, School of Medicine, University of Pennsylvania, Philadelphia, USA;Ovarian Cancer Research Center, School of Medicine, University of Pennsylvania, Philadelphia, USA;Abramson Family Cancer Research Institute, School of Medicine, University of Pennsylvania, Philadelphia, USA;Ovarian Cancer Research Center, School of Medicine, University of Pennsylvania, Philadelphia, USA;Department of Pathology and Laboratory Medicine School of Medicine, University of Pennsylvania, Philadelphia, USA;

关键词: Paclitaxel;    Gemcitabine;    Carboplatin;    Topotecan;    Chemotherapy Drug;   

DOI  :  10.1186/1479-5876-9-77

 received in 2010-11-23, accepted in 2011-05-25,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundTime-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.MethodsFour 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.ResultsPaclitaxel 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.ConclusionsTumor 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.

【 授权许可】

CC BY   
© Alagkiozidis et al; licensee BioMed Central Ltd. 2011