Abstract
Purpose: Mesothelioma has been regarded as a nonimmunogenic 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 toward 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 whether allogeneic lysate-pulsed DC immunotherapy is effective in mice and safe in humans.Experimental Design: First, 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 DCs per vaccination. DC vaccination consisted of autologous monocyte-derived DCs pulsed with tumor lysate from five 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% confidence interval (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. Clin Cancer Res; 24(4); 766-76. ©2017 AACR.
Highlights
Malignant pleural mesothelioma (MPM) is a highly lethal neoplasm for which new treatment options are urgently needed [1]
dendritic cell (DC) immunotherapy with allogeneic tumor lysate is effective in mice and safe and feasible in humans
Initial results have become available on the blockade of programmed death receptor (PD)-1/programmed death ligand 1 (PD-L1) in MPM showing single-agent response rates ranging between 9% and 25% [5]
Summary
Malignant pleural mesothelioma (MPM) is a highly lethal neoplasm for which new treatment options are urgently needed [1]. Reported randomized studies investigating immunotherapy [CTL-associated protein 4 (CTLA-4) inhibitor tremelimumab] and targeted treatment (FAK inhibition, defactinib) were found to be negative for the primary endpoint of an increase in overall survival [2, 3]. A number of new agents are being tested in early-phase studies in MPM, mostly focusing on immunotherapy with checkpoint inhibitors. Initial results have become available on the blockade of programmed death receptor (PD)-1/programmed death ligand 1 (PD-L1) in MPM showing single-agent response rates ranging between 9% and 25% [5]. Response rates to PD-1/PD-L1 inhibitors in these ranges have been found in other solid malignancies, such as non–small cell lung cancer An immune infiltrate including T cells is correlated
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