Rationale: We demonstrated before that autologous tumor lysate-pulsed dendritic cell-based immunotherapy in patients with malignant pleural mesothelioma is feasible, well-tolerated, and capable of inducing immunological responses against tumors. In our murine model we found that reduction of regulatory T cells with metronomic cyclophosphamide increased the efficacy of immunotherapy.
Objectives: To assess the decrease in number of peripheral blood regulatory T cells during combination therapy of low-dose cyclophosphamide and dendritic cell immunotherapy and to determine the induction of immunological responses with this treatment in mesothelioma patients.
Methods: Ten malignant pleural mesothelioma patients received metronomic cyclophosphamide and dendritic cell-based immunotherapy. During the treatment, peripheral blood mononuclear cells were analyzed for regulatory T cells and immunological responses.
Measurements and Main Results: Administration of dendritic cells pulsed with autologous tumor lysate combined with cyclophosphamide in mesothelioma patients was safe, the only side effect being moderate fever. Dendritic cell vaccination combined with cyclophosphamide resulted in radiographic disease control in eight of the ten patients. Overall survival was promising, with seven out of ten patients having a survival of ≥24 months and two patients still alive after 50 and 66 months. Low-dose cyclophosphamide reduced the percentage of regulatory T cells of total CD4 cells in peripheral blood from 9.43 (range 4.34-26.10) to 4.51 (range 0.27-10.30) after 7 days of cyclophosphamide treatment (P=0.02).
Conclusions: Consolidation therapy with autologous tumor lysate-pulsed dendritic cell-based therapy and simultaneously reducing the tumor-induced immune suppression is well-tolerated, and shows signs of clinical activity in mesothelioma patients. Clinical trial registration available at www.clinicaltrials.gov, ID NCT01241682.

This study was financially supported by Stichting Asbestkanker Rotterdam (www.asbestkanker.nl), Stichting Coolsingel, Stichting NutsOhra and the Mesothelioma Applied Research Foundation (MARF).
doi.org/10.1164/rccm.201508-1573OC, hdl.handle.net/1765/79524
American Journal of Respiratory and Critical Care Medicine
Department of Pulmonology

Cornelissen, R., Hegmans, J., Maat, A., Lambers, M., Bezemer, K., Hendriks, R., … Aerts, J. (2015). Extended Tumor Control After Dendritic Cell Vaccination With Low Dose Cyclophosphamide as Adjuvant Treatment in Patients With Malignant Pleural Mesothelioma. American Journal of Respiratory and Critical Care Medicine, 2015(December). doi:10.1164/rccm.201508-1573OC