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

Eur J Cardiothorac Surg. 2009 Mar;35(3):457-62. doi: 10.1016/j.ejcts.2008.11.030. Epub 2009 Jan 21.


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 microg cytosine phosphate guanosine oligodeoxynucleotide (CpG-ODN) (n=6), cisplatin-fibrin (n=6), cisplatin-fibrin+500 microg 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 mm(3) in the control group to 11.7 mm(3) in the cisplatin-fibrin group (p=0.004) and to 21.8mm(3) in the cisplatin-fibrin+CpG group (p=0.004). Pro-inflammatory cytokines (Interferon-gamma (IFN-gamma), 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.

MeSH terms

  • Adjuvants, Immunologic / administration & dosage
  • Animals
  • Cisplatin / administration & dosage
  • Combined Modality Therapy / methods
  • Cytokines / metabolism
  • Cytosine / metabolism
  • Immunotherapy / methods*
  • Interferon-gamma / metabolism
  • Male
  • Mesothelioma / immunology
  • Mesothelioma / pathology
  • Mesothelioma / therapy*
  • Neoplasm Recurrence, Local / pathology
  • Neoplasm Recurrence, Local / prevention & control*
  • Oligodeoxyribonucleotides / administration & dosage
  • Pleural Neoplasms / immunology
  • Pleural Neoplasms / pathology
  • Pleural Neoplasms / therapy*
  • Random Allocation
  • Rats
  • Rats, Inbred F344
  • Toll-Like Receptors / metabolism
  • Tumor Burden
  • Up-Regulation


  • Adjuvants, Immunologic
  • CPG-oligonucleotide
  • Cytokines
  • Oligodeoxyribonucleotides
  • Toll-Like Receptors
  • Interferon-gamma
  • Cytosine
  • Cisplatin