P2.06-21 Low Intratumoral Platinum Concentration is Associated with Unfavorable Clinical Outcome in Malignant Pleural Mesothelioma

Abstract

Background: Mesothelioma is a universally fatal malignancy with rising global incidence. Research to date has failed to make significant progress towards the control of mesothelioma, let alone its cure. An entirely different approach is needed. The anti-cancer properties of bacteria have been utilized as novel treatments for some cancers, including resistant bladder cancer in which Mycobacterium bovis BCG forms standard treatment. The use of bacteria presents an attractive approach in pleural mesothelioma, as there is strong evidence to suggest that an infection in the pleural space may increase survival in these patients. Our study aimed to capitalize on this phenomenon and determine whether bacteria or their products can be used as anti-mesothelioma agents. Method: We tested the efficacy of live (10 5 -10 7 CFU/mL) and attenuated (heat-killed) Streptococcus pneumoniae (n¼5) and Staphylococcus aureus (n¼5) clinical bacterial isolates obtained from patients with invasive bacterial infection and common laboratory reference strains (n¼4) against primary (n¼3) and established (n¼6) mesothelioma cell lines collected from patients with malignant pleural effusions. Benign mesothelial cells served as controls. Alternatively, conditioned medium (CM) (from S. aureus), or mutated bacteria (D39DPly or WCH43DGlpO), were added to mesothelioma cells. Cell viability was assessed using live/dead staining and analysed using flow cytometry. We also measured key cytokines involved in the pathobiology of mesothelioma and bacterial infection including; IL-1b, IL-6, VEGF and IL-8 using ELISA's. Result: Two of the live Staphylococcus aureus and Streptococcus pneumoniae isolates consistently killed all mesothelioma cell lines (median (IQR)%: 90.4(51.4-97.6)% and 99.6(99.4-99.8)% respectively). The same S. pneumoniae isolates also potently killed benign mesothelial cells (99.7(99.4-99.8)%). However, the two S. aureus isolates demonstrated significantly less efficacy against benign mesothelial cells (13.7(5.0-23.0)%), supporting the potential for targeted therapy. Attenuated clinical isolates and bacterial CM were not efficacious against mesothelioma cells. We observed increased cytokine levels in response to the most potent clinical isolates in all mesothelioma cell lines. In contrast, cytokine responses were greatly reduced in benign mesothelial cells. Pneumolysin and GlpO (a-glycerophosphate oxidase) did not mediate the cytotoxic effects of S. pneumoniae on mesothelioma cells as evidenced by comparison of mesothelioma cell killing to wild-type controls. Conclusion: We showed, for the first time, that clinical bacterial isolates can potently kill patient-derived mesothelioma cells with some specificity. Combined with our published data, which demonstrated the efficacy of a bacterial toxin against mesothelioma tumours in vivo, our data suggests that bacterial therapy is a promising novel approach for the treatment of mesothelioma and warrants further investigation.