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Open Access 01-12-2011 | Research

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

Authors: Ioannis Alagkiozidis, Andrea Facciabene, Marinos Tsiatas, Carmine Carpenito, Fabian Benencia, Sarah Adams, Zdenka Jonak, Carl H June, Daniel J Powell Jr, George Coukos

Published in: Journal of Translational Medicine | Issue 1/2011

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.

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Title: Time-dependent cytotoxic drugs selectively cooperate with IL-18 for cancer chemo-immunotherapy
Authors: Ioannis Alagkiozidis
Andrea Facciabene
Marinos Tsiatas
Carmine Carpenito
Fabian Benencia
Sarah Adams
Zdenka Jonak
Carl H June
Daniel J Powell Jr
George Coukos
Publication date: 01-12-2011
Publisher: BioMed Central
Published in: Journal of Translational Medicine / Issue 1/2011
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/1479-5876-9-77

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Conclusions

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