scholarly journals Immunotherapeutic Approaches in Malignant Pleural Mesothelioma

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2793
Author(s):  
Rita Terenziani ◽  
Silvia Zoppi ◽  
Claudia Fumarola ◽  
Roberta Alfieri ◽  
Mara Bonelli

Malignant pleural mesothelioma (MPM) is a rare and aggressive malignant disease affecting the mesothelium, commonly associated to asbestos exposure. The current therapeutic actions, based on cisplatin/pemetrexed treatment, are limited due to the late stage at which most patients are diagnosed and to the intrinsic chemo-resistance of the tumor. Another relevant point is the absence of approved therapies in the second line setting following progression of MPM after chemotherapy. Considering the poor prognosis of the disease and the fact that the incidence of this tumor is expected to increase in the next decade, novel therapeutic approaches are urgently needed. In the last few years, several studies have investigated the efficacy and safety of immune-checkpoint inhibitors (ICIs) in the treatment of unresectable advanced MPM, and a number of trials with immunotherapeutic agents are ongoing in both first line and second line settings. In this review, we describe the most promising emerging immunotherapy treatments for MPM (ICIs, engineered T cells to express chimeric antigen receptors (CARs), dendritic cells (DCs) vaccines), focusing on the biological and immunological features of this tumor as well as on the issues surrounding clinical trial design.

ESMO Open ◽  
2020 ◽  
Vol 4 (Suppl 2) ◽  
pp. e000669 ◽  
Author(s):  
Giuseppe Viscardi ◽  
Raimondo Di Liello ◽  
Floriana Morgillo

Malignant pleural mesothelioma is a rare and aggressive malignancy mostly associated with occupational asbestos exposure. Prognosis is poor and only highly selected patients may benefit from aggressive surgical management, also as part of a multimodal approach. In advanced disease, the combination of pemetrexed and platinum remains the only established treatment, while efficacy evidence of second line chemotherapy is lacking. Thus, a deeper knowledge of biology of the disease and more effective treatments are urgently needed. Refer to specialised centres with multidisciplinary expertise is mandatory, as well as inclusion of patients in clinical trials is advisable whenever possible. In all stages of disease focus on symptoms control is paramount.


2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20070-e20070
Author(s):  
Adithya Balasubramanian ◽  
Adrian Pick ◽  
Beena Kumar ◽  
Zdenka Prodanovic ◽  
Prashant Joshi ◽  
...  

e20070 Background: Malignant Pleural Mesothelioma (MPM) is a rare but fatal disease related to asbestos exposure, with historic survival in the order of 9 to 17 months. Chemotherapy is associated with only a modest benefit. The advent of immunotherapy has heralded significantly improved outcomes using checkpoint inhibitors in an as yet ill-defined cohort. We aim to identify predictive and prognostic biomarkers in a series of patients (pts) with MPM and describe survival data. Methods: A retrospective audit was undertaken of pts with MPM diagnosed between 2013 and 2017 at a single tertiary centre in Melbourne, Australia (Monash Health). Data relating to patient outcomes and clinicopathological features were obtained through medical reports. Further immunostains are being performed on archived tissue for PDL-1 status. Results: 65 pts were identified, of whom 52 (80.0%) were male. Median age was 73 years (range 44-90). 52 pts were noted to be ECOG 0-1. 42 pts (64.6%) were noted to have suspected asbestos exposure. Epithelioid MPM was the most common subtype, noted in 41 pts (63.1%) (table 1). 8 pts (12.3%) presented with stage IV disease. 16 pts (24.6%) received checkpoint inhibitor therapy, with 10 (63 %) in the second/third line setting. Median overall survival (OS) was 19.8 months (95% CI 13.3-26.3) in the whole cohort.Patient characteristics associated with poor OS were: presence of weight loss (P = 0.001), chest pain (p = 0.08) and ECOG 2 (p = 0.04). Pts with sarcomatoid histology who received immune checkpoint inhibitors in any line of treatment had significantly prolonged OS compared to other histologies. 3-year survival was 80% in this group while median OS was not reached (p = 0.04). This difference was not seen with other histologies. Conclusions: The evolving landscape of treatment in MPM appears to show promise in improving OS. In this unselected case series, our data is consistent with historic controls in terms of survival and prognostic factors. The finding of significantly improved survival with immune checkpoint inhibitors in the sarcomatoid histology is exciting and warrants further exploration. Further data on PDL1 status will be presented.


2018 ◽  
Author(s):  
Nicolas Alcala ◽  
Christophe Caux ◽  
Nicolas Girard ◽  
J.D. McKay ◽  
Francoise Galateau-Salle ◽  
...  

SummaryMalignant Pleural Mesothelioma (MPM) is an aggressive disease related to asbestos exposure, which incidence is expected to increase in the future, and with no effective therapeutic options. We have performed unsupervised analyses of publicly available RNAseq data for 297 MPM. We found that the molecular profile and the prognosis of this disease is better explained by a continuous model rather than by the current WHO classification into the epitheloid, biphasic and sarcomatoid histological types. The main source of variation of this continuum was explained by the immune and vascular pathways, with strong differences in the expression of pro-angiogenic genes and immune checkpoint inhibitors across samples. These data may inform future classifications of MPM and may also guide personalised therapeutic approaches for this disease.SignificanceMalignant Pleural Mesothelioma (MPM) is an aggressive disease with no effective therapeutic options. Unsupervised transcriptomic analyses of 297 MPM unveiled the vascular and the immune systems as key players in the prognosis of this disease, and identified potential therapeutic approaches for this disease targeting these pathways.


2020 ◽  
Vol 10 ◽  
Author(s):  
Yoshie Yoshikawa ◽  
Kozo Kuribayashi ◽  
Toshiyuki Minami ◽  
Masaki Ohmuraya ◽  
Takashi Kijima

Malignant pleural mesothelioma (MPM) is strongly associated with occupational or environmental asbestos exposure and arises from neoplastic transformation of mesothelial cells in the pleural cavity. The only standard initial treatment for unresectable MPM is combination chemotherapy with cisplatin (CDDP) and pemetrexed (PEM). Further, CDDP/PEM is the only approved regimen with evidence of prolonged overall survival (OS), although the median OS for patients treated with this regimen is only 12 months after diagnosis. Thus, the development of new therapeutic strategies has been investigated for approximately 20 years. In contrast to recent advances in personalized lung cancer therapies, diagnostic and prognostic biomarker research has just started in mesothelioma. Epigenetic alterations include DNA methylation, histone modifications, and other chromatin-remodeling events. These processes are involved in numerous cellular processes including differentiation, development, and tumorigenesis. Epigenetic modifications play an important role in gene expression and regulation related to malignant MPM phenotypes and histological subtypes. An immune checkpoint PD-1 inhibitor, nivolumab, was approved as second-line therapy for patients who had failed initial chemotherapy, based on the results of the MERIT study. Various clinical immunotherapy trials are ongoing in patients with advanced MPM. In this review, we describe recent knowledge on epigenetic alterations, which might identify candidate therapeutic targets and immunotherapeutic regimens under development for MPM.


Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1138
Author(s):  
Martina Schiavello ◽  
Elena Gazzano ◽  
Loredana Bergandi ◽  
Francesca Silvagno ◽  
Roberta Libener ◽  
...  

Although asbestos has been banned in most countries around the world, malignant pleural mesothelioma (MPM) is a current problem. MPM is an aggressive tumor with a poor prognosis, so it is crucial to identify new markers in the preventive field. Asbestos exposure induces oxidative stress and its carcinogenesis has been linked to a strong oxidative damage, event counteracted by antioxidant systems at the pulmonary level. The present study has been focused on some redox-sensitive transcription factors that regulate cellular antioxidant defense and are overexpressed in many tumors, such as Nrf2 (Nuclear factor erythroid 2-related factor 2), Ref-1 (Redox effector factor 1), and FOXM1 (Forkhead box protein M1). The research was performed in human mesothelial and MPM cells. Our results have clearly demonstrated an overexpression of Nrf2, Ref-1, and FOXM1 in mesothelioma towards mesothelium, and a consequent activation of downstream genes controlled by these factors, which in turn regulates antioxidant defense. This event is mediated by oxidative free radicals produced when mesothelial cells are exposed to asbestos fibers. We observed an increased expression of Nrf2, Ref-1, and FOXM1 towards untreated cells, confirming asbestos as the mediator of oxidative stress evoked at the mesothelium level. These factors can therefore be considered predictive biomarkers of MPM and potential pharmacological targets in the treatment of this aggressive cancer.


Author(s):  
Jonathan D. Moore

Our hopes of using the power of the immune system to control tumours have been partially fulfilled with anti-PD1 antibodies and other checkpoint inhibitors and the use of engineered T cells targeting lineage-specific surface markers with chimeric antigen receptors. Can these successes be generalised? Therapeutic cancer vaccines aim to educate or re-educate the immune system to recognise tumour specific or tumour associated antigens. After many false dawns, some positive data for the effectiveness of such an approach is starting to emerge in advanced solid tumours, albeit as combination therapies with checkpoint inhibitors. But is the field targeting the right antigens? Interventions using the most effective vaccine platforms to target certain sets of antigens in patients with low disease burden might bring impressive long-term benefits to patients as single agents.


2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Cheng-Kuan Lin ◽  
Yu-Ying Chang ◽  
Jung-Der Wang ◽  
Lukas Jyuhn-Hsiarn Lee

Objective. This paper aimed to determine the standardised incidence ratio (SIR) of malignant pleural mesothelioma (MPM) in workers exposed to asbestos in Taiwan.Methods. All workers employed in asbestos-related factories and registered by the Bureau of Labour Insurance between 1 March, 1950, and 31 December, 1989, were included in the study and were followed from 1 January, 1980, through 31 December, 2009. Incident cases of all cancers, including MPM (ICD-9 code: 163), were obtained from the Taiwan Cancer Registry. SIRs were calculated based on comparison with the incidence rate of the general population of Taiwan and adjusted for age, calendar period, sex, and duration of employment.Results. The highest SIR of MPM was found for male workers first employed before 1979, with a time since first employment more than 30 years (SIR 4.52, 95% CI: 2.25–8.09). After consideration of duration of employment, the SIR for male MPM was 5.78 (95% CI: 1.19–16.89) for the workers employed for more than 20 years in asbestos-related factories.Conclusions. This study corroborates the association between occupational asbestos exposure and MPM. The highest risk of MPM was found among male asbestos workers employed before 1979 and working for more than 20 years in asbestos-related factories.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20565-e20565
Author(s):  
Ervin Saúl Enciso López ◽  
Efrain Isaias Camarin Sanchez ◽  
Daniela Vazquez Juarez ◽  
Alejandro Noguez-Ramos ◽  
Daniela Shveid Gerson ◽  
...  

e20565 Background: Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer. Prognosis is generally poor, with a median overall survival (mOS) of approximately 12 months. MPM appears to be directly linked to immunosuppressive mechanisms, leading to use of checkpoint inhibitors for patients with this disease. Methods: We performed a retrospective chart review of patients with MPM at our institution between January 2015 to December 2020. All patients were over 18 years at the time of diagnosis of mesothelioma, a total of 8 patients were retrieved from the pathology database of The American British Cowdray Medical Center. The clinical-pathologic features collected were sex, age, performance status, risk factors, pTNM stage (AJCC 8th edition), histology type, sintomatology of onset, metastases sites and treatment. Clinical response rate and other outcomes were assessed. Descriptive statistics were used to describe a patient's demographic and disease characteristics. Results: 8 patients, aged 49 to 71 years (median of 65) at diagnosis of MPM were treated in our center. Both sex presented 4 patients in total. An identifiable risk factor was recorded in 4 patients (2 with asbesto exposure and 2 with heavy smoking). 7 patients (87.5%) had PS 0 or 1, the remaining has PS 2. The clinical stage at diagnosis was unresectable in 7 patients. 3 patients were assessed with PD-L1 expression (SP263 or 22C3), only one with expression of 20%. All patients received at least one scheme of chemotherapy prior to receiving immunotherapy, 25% received bevacizumab/platinum/anti-folate agents. Checkpoint inhibitors were introduced as a second line in 20% and in 80% has a third or more lines. Pembrolizumab was used in 20% and Nivolumab in 80%. The tumor responses with immunotherapy were as follows: partial response 12.5%, stable disease 75% and progressive disease 12.5%. Median progression-free survival of the first line treatment was 18.9 months (4.6-33.6 months), and for the line with checkpoint inhibitors was 11.2 weeks (7-21.2). In the full cohort, mOS was 37.0 months (95% CI:14.5-39.6). According to histology, the mOS for epithelioid-type was 36.6 months and for biphasic-type was 14.6 months (p = 0.42). mOS was 37.0 months for the group with immunotherapy and 15.0 months for those with standard chemotherapy (p = 0.14). The most frequently reported immune mediated adverse events were hypothyroidism and colitis (each one with one patient). Conclusions: In this real-world analysis, mOS was superior to those obtained in the MAPS2 trial (mOS 11.9 months), despite the fact that 80% of the population that received immunotherapy was in third or more lines. Limitations include limited numbers of patients, retrospective review, single institution, and inclusión of many heavily pretreated patients. Also molecular and immunohistochemical results such as PD-L1 status were only available on a limited number of patients.


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