IMMUNOTHERAPY combined with chemotherapy and in-depth analysis of tumor genomics can improve the survival of patients with pleural mesothelioma, a rare tumor that attacks the pleura, caused in almost all cases by occupational exposure to asbestos (or asbestos). It is a bad tumor, given that about 10% of those affected survive 5 years after diagnosis in Italy.
Today, malignant pleural mesothelioma can count on rather limited possibilities of cure, but a multicentre phase 2 study (called PrE0505) could pave the way for new treatments. The first results are published on Nature Medicine by researchers at the Johns Hopkins Kimmel Cancer Center and the Bloomberg-Kimmel Institute for Cancer Immunotherapy. The authors gave 55 patients with unresectable pleural mesothelioma a dose of durvalumab (a monoclonal antibody PD-L1 inhibitor) in combination with pemetrexed (a drug that works by inhibiting the activity of enzymes involved in the production of DNA and Rna) and platinum (cisplatin or carboplatin), for up to six cycles. The result was that the mean overall survival was 20.4 months (i.e. significantly longer than the historically observed 12 months), and for patients with epithelioid tumors, i.e. the most common subtype of pleural mesothelioma, of 24.3 months.
More mutations, better responses
Patients with tumors with a higher burden of immunogenic mutations (i.e., with more changes in the tumor genome capable of causing an immune response) and a more diverse repertoire of T cells capable of recognizing and destroying were the most responsive to combination therapy. cancer cells, and those with alterations in the genes involved in DNA damage repair. “The PrE0505 study indicates that durvalumab administered simultaneously with platinum-based chemotherapy is promising and that responses are controlled by tumor genomics,” said Patrick Forde, author of the study and director of the research program. thoracic cancer clinic at the Johns Hopkins Kimmel Cancer Center. “For patients with epithelioid pleural mesothelioma – he added – survival has exceeded two years and in some of these patients we still do not register disease progression”.
Phase 3 of the study
Of course, the study continues: in fact, immuno-chemotherapy in combination with the in-depth genomic characterization of tumors compared with chemo alone is now the subject of further investigations in an international phase III clinical trial. “Our findings not only point to a potential new effective therapy for mesothelioma, but also explain, at the molecular level, why patients respond,” said another of the authors, Valsamo Anagnostou, director of the Johns Hopkins Thoracic Oncology Biorepository. Kimmel Cancer Center and associate professor of Oncology at Johns Hopkins University School of Medicine. “We discovered – added Anagnostou – that some truly unique characteristics that concern both the patient’s and the tumor’s genomics, and that seem to guide the clinical response. Furthermore, patients who get good results with chemo-immunotherapy are those with germline mutations in genes that predispose to cancer. All this – he concluded – has the potential to be translated into new treatment strategies for patients with mesothelioma ”.
Mesothelioma, asbestos and Italy
Mesothelioma is cancer of the tissue that lines the internal organs. Every year in Italy there are approximately 1,800 new cases of disease, with which in our country today roughly 2,700 people live, twice out of three men. In 95% of cases mesothelioma is caused by exposure to asbestos (or asbestos, from the Greek indestructible asbestos) above all by inhalation and in over 90% of cases it is mesothelioma of the pleura, which in Italy is a professional disease listed. , which means his professional origin is supported by legal presumption. In other words: for the cause-effect link with the onset of mesothelioma to be recognized, it is therefore sufficient to demonstrate that they have been used for processes that have exposed the action of asbestos fibers. This mineral fibrous substance has been used for decades in construction, the automotive industry, paint production, the manufacture of trains or ships and much more, peaking between 1970 and 1990. Starting in 1990, asbestos was banned in many Western countries, including ours: in Italy, Law 257 of 1992 257/1992 prohibits the production and use on the entire national territory of all products containing asbestos. Nonetheless, we are still among the countries most affected by pleural mesothelioma today. The reason is that this disease has a very long latency time: we are talking about decades, even 40 years.
Workers and non-workers
The risk of developing pleural mesothelioma increases both among workers exposed to asbestos and among people with non-occupational exposure. According to the data of the VI Report of the National Mesothelioma Registry (ReNaM) which reports the incidence and exposure data to asbestos for cases of malignant mesothelioma detected by the network of Regional Operating Centers, non-occupational exposure is responsible for 10.8 % of pleural mesothelioma cases in Italy.
A peak expected in the near future
Once inhaled, asbestos fibers are deposited in healthy tissues where they attract macrophages, our scavenger cells, which however are unable to remove them: their presence slowly causes a chronic inflammatory state which, in turn, through several complex steps , it can transform healthy cells into cancer cells. Given the latency times and periods of maximum use of asbestos, various models predict a peak in the incidence of mesothelioma on the national territory between 2020 and 2030, that is, in these years. We do not have specific tests available that allow early detection of mesothelioma in the absence of symptoms, which means that today there are no validated screening tests. But in Italy there are surveillance and assistance programs, particularly in the case of occupational exposure.