Autologous Dendritic Cells Pulsed with Allogeneic Tumor Cell Lysate in Mesothelioma: From Mouse to Human

Abstract

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. 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. 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). DC immunotherapy with allogeneic tumor lysate is effective in mice and safe and feasible in humans. .

Photodynamic Therapy-Based Dendritic Cell Vaccination Suited to Treat Peritoneal Mesothelioma

“…The use of mesothelioma cell lines, combined with PDT, to induce immunogenic cell death may, thus, help to generalize DC-based vaccination protocols. Recently, Aerts and colleagues confirmed that the use of allogenic tumor lysate was feasible [17] and launched a multicenter, randomized, phase II/III study of dendritic cells loaded with allogeneic tumor cell lysate [43]. The use of PDT to kill different human mesothelioma cell lines, instead of more conventional freeze-thaw protocols, would represent a minor adaptation to such protocol with a potentially relevant gain in efficacy.…”

“…Ex vivo pulsed DC may indeed overcome the problems of low immunogenicity and deficiency in antigen presentation [15]. Several small clinical trials have already explored this possibility using autologous [16] or allogenic [17] MM lysate-pulsed DCs. Recently, the optimization of DC immunotherapy was proposed to integrate the concept of immunogenic cell death; in particular, to induce a superior T helper 1 (TH1)-mediated immunity [18].…”

Malignant Peritoneal Mesothelioma: Patterns of Care and Survival in The Netherlands. A Population Based Study.

“…35 Earlier, DCBI showed promising results for patients with pleural mesothelioma. [36][37][38] By simultaneously seeking attention for this clinical trial and MPM in general, awareness of treatment possibilities and the number of referrals has increased.…”

Genome‐wide expression profiling‐based copy number variations and colorectal cancer risk in Chinese

“…Recently, DC vaccination has been considered as promising tumor treatment. A phase‐I trial observed the impressive objective response of a tumor reduction of about 70% at 6 weeks posttreatment in a patient with malignant pleural mesothelioma by providing enhanced tumor antigen presentation with DC vaccination through the mechanism of increasing the number of B, CD4 + and CD8 + T lymphocytes in peripheral blood . Besides, the combination of transgenic T‐cell receptor‐reactive adoptive cellular therapy with DC vaccination could result in transient antitumor activity in patients with advanced sarcoma or melanoma .…”