Abstract
Malignant pleural mesothelioma (MPM) is an aggressive cancer with a very poor prognosis. Recently, immune checkpoint inhibition (ICI) has taken center stage in the currently ongoing revolution that is changing standard-of-care treatment for several malignancies, including MPM. As multiple arguments and accumulating lines of evidence are in support of the existence of a therapeutic synergism between chemotherapy and immunotherapy, as well as between different classes of immunotherapeutics, we designed a multicenter, single-arm, phase I/II trial in which both programmed-death-ligand 1 (PD-L1) inhibition and dendritic cell (DC) vaccination are integrated in the first-line conventional platinum/pemetrexed-based treatment scheme for epithelioid MPM patients (Immuno-MESODEC, ClinicalTrials.gov identifier NCT05765084). Fifteen treatment-naïve patients with unresectable epithelioid subtype MPM will be treated with four 3-weekly (±3 days) chemo-immunotherapy cycles. Standard-of-care chemotherapy consisting of cisplatinum (75mg/m2) and pemetrexed (500mg/m2) will be supplemented with the anti-PD-L1 antibody atezolizumab (1200 mg) and autologous Wilms’ tumor 1 mRNA-electroporated dendritic cell (WT1/DC) vaccination (8–10 x 106 cells/vaccination). Additional atezolizumab (1680 mg) doses and/or WT1/DC vaccinations (8–10 x 106 cells/vaccination) can be administered optionally following completion of the chemo-immunotherapy scheme. Follow-up of patients will last for up to 90 days after final atezolizumab administration and/or WT1/DC vaccination or 24 months after diagnosis, whichever occurs later. The trial’s primary endpoints are safety and feasibility, secondary endpoints are clinical efficacy and immunogenicity. This phase I/II trial will evaluate whether addition of atezolizumab and WT1/DC vaccination to frontline standard-of-care chemotherapy for the treatment of epithelioid MPM is feasible and safe. If so, this novel combination strategy should be further investigated as a promising advanced treatment option for this hard-to-treat cancer.
Introduction
Malignant pleural mesothelioma (MPM) is a rare and highly aggressive cancer arising from the mesothelial surfaces of the pleural cavities. The occurrence of MPM is tightly associated with prior, mostly professional, asbestos exposure [1]. Although preventive measures to limit asbestos use and exposure have been around for several decades, the incidence of MPM is only expected to decrease very slowly for several years ahead due to the long latency between asbestos exposure and MPM development as well as the persistence of environmental exposure [2, 3]. Until recently, patients with advanced or unresectable disease had limited treatment options, with doublet chemotherapy consisting of a platinum compound, either cisplatin or carboplatin, and a folate antimetabolite, either pemetrexed or raltitrexed, being the only available first-line therapy, resulting in a dismal 5-year survival rate of less than 10% and a median overall survival (mOS) of 12.1–16.1 months [4–7].
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