Immuno-chemotherapy reduces recurrence of malignant pleural mesothelioma: an experimental setting.
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.
Ampollini
Luca
L
Thoracic Surgery, University Hospital of Zurich, Switzerland.
Soltermann
Alex
A
Felley-Bosco
Emanuela
E
Lardinois
Didier
D
Arni
Stephan
S
Speck
Roberto F
RF
Weder
Walter
W
Opitz
Isabelle
I
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy / Q000379:methods; D016207:Cytokines / Q000378:metabolism; D003596:Cytosine / Q000378:metabolism; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D008654:Mesothelioma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D009364:Neoplasm Recurrence, Local / Q000473:pathology / Q000517:prevention & control*; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D010997:Pleural Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D051193:Toll-Like Receptors / Q000378:metabolism; D047368:Tumor Burden; D015854:Up-Regulation
D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D016207:Cytokines; D009838:Oligodeoxyribonucleotides; D051193:Toll-Like Receptors; D007371:Interferon-gamma; D003596:Cytosine; D002945:Cisplatin