Dr. Ceresoli achieved his MD at Medical School of the University of Milan, Italy. He completed his Residency in Medical Oncology at San Raffaele Scientific Institute in Milan from 1992-1996. He is currently Head of the Thoracic and GU Oncology Unit at Humanitas Institute in Bergamo, Italy. Dr. Ceresoli is part of the Faculty of the European School of Oncology for thoracic cancers. His clinical and research activity is mainly in the field of malignant pleural mesothelioma. He has been principal investigator in several trials on malignant pleural mesothelioma, and has treated many mesothelioma patients over the span of his career. He has been the Principal Investigator of the STELLAR trial of TTFields plus chemotherapy in unresectable malignant pleural mesothelioma.
Malignant pleural mesothelioma (MPM) is an aggressive disease with a dismal prognosis, whose incidence is expected to rise in many countries worldwide. Only a minority of patients is suitable for multimodality strategies including surgery. Chemotherapy with cisplatin/carboplatin and pemetrexed has represented the standard treatment for unresectable MPM for many years. Studies evaluating anti-angiogenic drugs such as bevacizumab or nintedanib added to cisplatin and pemetrexed have resulted in no or marginal improvement with increased toxicity. Recently, immunotherapy with immune checkpoint inhibitors alone or in combination with chemotherapy was evaluated as upfront treatment of unresectable MPM. In the Checkmate 743 trial, a phase 3 randomized study of first-line nivolumab + ipilimumab vs platinum doublet chemotherapy, overall survival (OS) was significantly improved with immunotherapy. The survival benefit was observed mainly in non-epithelioid histologies. Phase III trials of immunotherapy + chemotherapy vs chemotherapy alone are ongoing (IND227 trial: chemotherapy vs chemotherapy + pembrolizumab; DREAM trial: chemotherapy vs chemotherapy + durvalumab), and their results are eagerly awaited.
Tumor Treating Fields (TTFields) are a loco-regional treatment comprising low-intensity, intermediate frequency alternating electric fields delivered non-invasively to the tumor by transducer arrays applied to the skin surrounding the tumor. TTFields act with an anti-mitotic mechanism, by disruption of the mitotic spindle during metaphase and interference with the migration of intracellular polarized macromolecules and organelles during telophase. Preclinical data have shown that mesothelioma cell lines are among the most sensitive to TTFields at the optimal frequency of 150 kHz, and that TTFields increase the activity of both cisplatin and pemetrexed. TTFields delivered to the thorax in combination with platinum/pemetrexed chemotherapy have been recently explored as first-line treatment for patients with unresectable MPM. The results of the phase 2 STELLAR trial showed in 80 enrolled patients that the combination of TTFields at a frequency of 150 kHz with pemetrexed and cisplatin or carboplatin is an active and safe option in this disease setting. Median OS was 18.2 months, with 62% of patients alive at one year and a 2-year OS of 42%. Patients with epithelioid tumors survived longer, with a median OS of 21.2 months versus 12.1 months for those with non-epithelioid tumors. The addition of TTFields to standard chemotherapy was not associated with an increase in systemic toxicity. The only adverse event related to the device was skin irritation underneath the transducer arrays. Grade 1-2 skin toxicity was observed in 53 (66%) of patients; only 4 (5%) had a grade 3 skin toxicity, leading to temporary or permanent interruption of the treatment. In the majority of cases skin toxicity resolved with topical corticosteroids, short treatment breaks and a regular shifting of the arrays applied to the skin. Interestingly, recent preclinical data have shown a potential interaction of TTFields with the immune tumor microenvironment. In in vitro models, several cancer cell lines treated with TTFields exhibited increased markers of immunogenic cell death such as calreticulin and high-mobility group box 1 (HMGB1) protein. Moreover, in mice orthotopically implanted with LLC-1 cells, TTFields in combination with anti-PD-1 therapy enhanced antigen-presenting cell (CD45+) and T cell recruitment, and led to a significant decrease in tumor volume. These data suggest that TTFields-induced cell death can be immunogenic and therefore TTFields may be suitable for combination with anti-PD-1/PD-L1 therapy.