Immunotherapy with dendritic cells as a second-line therapy in advanced pleural mesothelioma.

Background: Malignant pleural mesothelioma (MPM) is an aggressive disease with an unfavorable prognosis. The current front-line treatment for nonoperable stages is cisplatinum in combination with pemetrexed chemotherapy. The reported median overall survival times are less than 15 months. After failure of first-line therapy there is currently no proven effective therapy, whereas potential side effects from further treatments may impair quality of life. In those cases, we report that immunotherapy with monocyte-derived dendritic cells (MoDC) can be effective without significant impact on life quality. Methods: After isolating monocytes from peripheral blood of n=14 patients with stage 4 MPM who failed first-line chemotherapy, MoDC were generated using standard protocols. The MoDC were primed on day 5 with tumor-lysate and co-cultured with toll-like receptor ligands to induce a TH1-polarization of the MoDC. In one case, an allogeneic cell line lysed by the oncolytic Newcastle disease virus (NDV) was used. This patient received an NDV injection one day before the DC administration. In general, the MoDC were harvested on day 7 and administered to the patients, intradermally. Results: We were able to induce a clinical response in 29% of the patients (n=3 stabilization, 1 partial remission). The median survival after onset of DC-therapy was 7 months (1-26 months) and 24 months (7-33 months) after primary diagnosis. The therapy was well tolerated without having any major side effect. Interestingly, the patient showing a partial remission received the NDV-modified vaccine. IFN-gamma Elispot analyses from patients who received NDV injections and NDV-modified MoDC show that MoDC primed with NDV-lysed tumor cells can induce a specific CD4 and CD8 T-cell response against the NDV-lysed tumor cells whereas healthy donors show no specific T-cell response. Conclusions: Immunotherapy with dendritic cells may prolong the overall survival of patients with MPM after failure of first-line therapy without significant impact on the quality of life. For the first time, we demonstrated that NDV is able to infect MPM cells, leading to lysis of these cells.