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Immuno-chemotherapy reduces recurrence of malignant pleural mesothelioma: an experimental setting

^a Thoracic Surgery, University Hospital of Zurich, Switzerland
^b Department of Pathology, Zurich, Switzerland
^c Laboratory of Molecular Oncology, Zurich, Switzerland
^d Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, Switzerland

Received 8 June 2008; received in revised form 13 October 2008; accepted 12 November 2008.

^_* Corresponding author. Address: Division of Thoracic Surgery, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland. Tel.: +41 44 255 8802; fax: +41 44 255 8805. (Email: walter.weder{at}usz.ch).

Objective: To assess the effect of immuno-chemotherapy on the extent of local tumour recurrence in an established rat model of malignant pleural mesothelioma (MPM). Methods: Six days after subpleural inoculation of a syngeneic MPM cell line Interleukin-45 (IL-45), left-sided pneumonectomy and resection of the tumour nodule was performed. Animals were randomised into four treatment groups for intrapleural therapy: control (n = 6), 500 µg cytosine phosphate guanosine oligodeoxynucleotide (CpG-ODN) (n = 6), cisplatin-fibrin (n = 6), cisplatin-fibrin + 500 µg CpG (n = 6). Six days later the volume of tumour recurrence was assessed, which was the primary endpoint. Secondary endpoints were quantification of the ratio host/tumour cells in the local recurrence and cytokine expression profile in the tumour tissue by real time quantitative PCR (qPCR). T lymphocyte subpopulations in the tumour recurrence tissue were evaluated by immunohistochemistry. Treatment-related toxicity was monitored by measuring blood chemistry and complete blood count. Results: The volume of tumour recurrence was significantly reduced from 610 mm³ in the control group to 11.7 mm³ in the cisplatin-fibrin group (p = 0.004) and to 21.8 mm³ in the cisplatin-fibrin + CpG group (p = 0.004). Pro-inflammatory cytokines (Interferon- (IFN-), Interleukin-6 (IL-6), Interleukin-12 (IL-12)) were increased after treatment with cisplatin-fibrin + CpG in comparison to cisplatin-fibrin alone but differences were not statistically significant. We found a higher ratio of host/tumour cells in the cisplatin-fibrin + CpG group (45/55%) compared to the cisplatin-fibrin group (27/73%). In comparison to the control group, animals treated with cisplatin-fibrin + CpG showed a higher number of CD8+ T-cells in the tumour tissue. No significant treatment-related toxicity was observed. Conclusions: Adjuvant treatment with chemotherapy or immuno-chemotherapy leads to significant reduction of mesothelioma recurrence after surgery in this rat MPM model. Immuno-chemotherapy resulted in an increased recruitment of inflammatory cells to the site of tumourigenesis and elicited higher level of tumour growth inhibiting cytokines.

Key Words: Mesothelioma • Immunotherapy • Cisplatin • Intrapleural • Toll-like receptor • CpG-ODN