Autologous dendritic cells pulsed with allogeneic tumor cell lysate in mesothelioma: From mouse to human

Purpose: Mesothelioma has been regarded as a non-immunogenic tumor, which is also shown by the low response rates to treatments targeting the PD-1/PD-L1 axis.  Previously, we demonstrated that autologous tumor lysate-pulsed dendritic cell (DC) immunotherapy increased T-cell response towards malignant mesothelioma. However, the use of autologous tumor material hampers implementation in large clinical trials, which might be overcome by using allogeneic tumor cell lines as tumor antigen source.  The purpose of this study was to investigate if allogeneic lysate pulsed DC immunotherapy is effective in mice and safe in humans. Experimental Design: Firstly, in two murine mesothelioma models, mice were treated with autologous DCs pulsed with either autologous or allogeneic tumor lysate, or injected with PBS (negative control). Survival and tumor-directed T cell responses of these mice were monitored.  Results were taken forward in a first-in-human clinical trial, in which 9 patients were treated with 10, 25 or 50 million DC per vaccination. DC vaccination consisted of autologous monocyte-derived DC pulsed with tumor lysate from 5 mesothelioma cell lines. Results: In mice, allogeneic lysate-pulsed DC immunotherapy induced tumor-specific T cells and led to an increased survival, to a similar extent as DC immunotherapy with autologous tumor lysate. In the first-in-human clinical trial, no dose limiting toxicities were established and radiographic responses were observed. Median PFS was 8.8 months (95% CI 4.1-20.3) and median OS not reached (median follow up 22.8 months). Conclusions: DC immunotherapy with allogeneic tumor lysate is effective in mice and safe and feasible in humans.

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