Malignant pleural mesothelioma (MPM) stands as an aggressive neoplasm arising from mesothelial cells that constitute the serous lining of the pleural cavity. Presently, it is regarded as a rare malignancy, with an approximate incidence of 1.83 cases per 100,000 individuals per year.1 Classification of MPM can be done into three distinct subtypes based on histological morphology: epithelioid, sarcomatoid, or biphasic.

In the contemporary scenario, all forms of asbestos are classified as Class 1 carcinogens by the International Agency for Research on Cancer. A well-established causal relationship between asbestos exposure and MPM development exists, albeit with an average latency period of around 40 years.2 While 85% of mesotheliomas can be attributed to occupational asbestos exposure, merely 10% of those exposed individuals will eventually develop MPM. Moreover, asbestos exposure is also linked to lung cancer, and the combination of smoking and exposure escalates the risk of lung cancer development by 10–100 times compared to non-exposed individuals.3 Despite asbestos being banned in many countries, its extraction and commercialization persist as latent issues, particularly in emerging economies, sustaining the global incidence of exposure.1 This, in turn, portends an exponential surge in mesothelioma cases in these regions due to its unregulated utilization.4

The median age at MPM diagnosis hovers around 70–75 years, displaying a male-to-female ratio of 3:1.5 According to Surveillance, Epidemiology, and End Results (SEER) data, the median reported survival rates for these patients range between 8 and 12 months in recent decades,6 and between 12 and 18 months in the context of the latest clinical trials.7 Estimated global survival rates at 1 and 3 years stand at 40% and 10%, respectively.8 As per the American Cancer Society, around 40,000 individuals succumb annually worldwide due to this pathology.9 Factors predicting outcomes include tumor stage at presentation, functional status, and response to cytostatic treatment.10 This data underscores the critical significance of early detection and optimized therapeutic interventions in enhancing patient prognosis.

In this ever-evolving landscape of mesothelioma, where meticulous clinical evaluation meets cutting-edge research, novel approaches are being harnessed to ameliorate patient outcomes and provide hope for those battling this complex ailment. Continued investigation, collaboration, and interdisciplinary efforts will undoubtedly illuminate new avenues for tackling the challenges posed by malignant pleural mesothelioma.

The scrutiny of mutational landscapes within MPM has assumed pronounced significance, serving as a pivotal tool to unearth genetic aberrations or mutational changes. Specifically, the integration of Immune Checkpoint Inhibitors (CPIs) has entrenched itself as a promising therapeutic strategy for these patients.1

Recent years have witnessed a revolution in the management of diverse tumor types through the utilization of CPIs. The fundamental premise underlying immunotherapy involves harnessing the host's immune system to wage a concerted assault against malignant cells. Current investigations in the realm of CPIs encompass not only those targeting T-cell responses or activating T-cell pathways but also the utilization of cytokines such as IL-12 and IL-15, therapeutic vaccines, ablation of immunosuppressive cells, and modulation of other constituents of the immune cascade.11

In the specific context of MPM, a range of promising CPIs have surfaced. On one front stands CTLA-4 (Cytotoxic T-lymphocyte-associated protein 4), a receptor located on the surface of T-cells. Its pivotal role hinges on immune response regulation, achieved by curbing T-cell activation. CTLA-4 interacts with specific ligands on other immune cells, such as antigen-presenting cells, transmitting inhibitory signals that curtail T-cell activity. This finely orchestrated equilibrium sustains immune response balance and averts autoimmunity.12 Empirical evidence underscores augmented suppression of tumor growth upon administration of monoclonal anti-CTLA4 antibodies in murine MPM models.13

On another axis emerges PD-1 (programmed cell death protein 1), expressed on the surface of T-cells as well as other immune constituents like B-cells and dendritic cells. During immune response activation, PD-1 forms interactions with its ligands PD-L1 (programmed death-ligand 1) and PD-L2 (programmed death-ligand 2), orchestrating a cascade that transmits inhibitory signals back to the T-cell itself.14 Notably, heightened PD-L1 expression has been documented in MPM,15 with this expression being subject to variations contingent upon histological subtypes. Notably, this elevated expression extends to 21% of epithelial subtypes, 94% of sarcomatoid subtypes, and 57% of biphasic subtypes.16

The elucidation of these multifaceted interactions between CPIs, immune microenvironment, and the unique cellular terrain of MPM shines a light on the promising prospects of leveraging these mechanisms in the quest to refine therapeutic approaches and ultimately augment patient outcomes.

The comprehension of cytogenetic and molecular facets in mesothelioma carries a profound complexity, primarily attributed to the infrequent occurrence of genetic alterations and the substantial heterogeneity across patients.17–19 Nonetheless, high-throughput analyses have revolutionized molecular characterization, unveiling a deeper understanding of its biological intricacies and the potential therapeutic targets within MPM.

While mutations in specific genes remain relatively rare, noteworthy changes have been identified in pivotal genetic pathways, including those encoding the cyclin-dependent kinase inhibitor 2A (CDKN2A), neurofibromin 2 (NF2), and the BRCA1-associated protein 1 (BAP1).20–22 Unlike the majority of other cancers, TP53 mutations are infrequent in mesothelioma, occurring in less than 10% of cases17,23; however, when isolated, these mutations correspond to a poorer survival rate.24

In approximately 45% of mesothelioma cases, CDKN2A is eradicated, encoding two cell cycle regulators: p16INK4a, which inhibits the cyclin-dependent kinase 4 and 6 phosphorylation of the retinoblastoma protein (RB); and p14ARF, preventing p53 degradation by Mdm2.

Notably, germline mutations in BAP1 predispose individuals to malignant pleural mesothelioma.25 BAP1 plays a pivotal role as a regulator of gene-environment interactions.26 The loss of BAP1 amplifies the susceptibility of fibroblasts and mesothelial cells to external agents like asbestos, thereby fostering mesothelioma development. Intriguingly, patients with mesothelioma harboring germline mutations in BAP1 exhibit significantly improved prognosis, although the underlying mechanisms remain enigmatic.27

NF2 encodes Merlin, a protein that exerts negative regulation over receptor-dependent mitogenic signaling and the activity of phosphatidylinositol 3-kinase (PI3K)-AKT, while also activating the Hippo pathway.28 Intriguingly, NF-κB has been unveiled as a survival factor in mutated human mesothelial cells and human mesothelioma cells, concurrently serving as a factor of resistance to chemotherapeutic treatment.29,30

This mosaic of genetic and molecular underpinnings underscores the intricate tapestry of mesothelioma and unveils novel avenues for therapeutic intervention, transforming the landscape of mesothelioma treatment strategies and propelling us toward more targeted and efficacious therapies.

The aggressiveness of malignant pleural mesothelioma (MPM), the high percentage of irresectability upon diagnosis, and the lack of highly effective treatments contribute to long-term survival outcomes remaining close to 10% at the 5-year mark post-diagnosis.31

Until October 2020, platinum-based agents in combination with folate antimetabolites such as pemetrexed have stood as the sole approved first-line treatment regimens for MPM since 2004.32–34

The pivotal Phase III CheckMate 743 trial in 2021 ushered in a new era for first-line therapy by introducing immunotherapy. Following the approval of the combined treatment of nivolumab with ipilimumab, the study showcased a remarkable 50% improvement in 2-year overall survival (41% vs. 27%) compared to previously described chemotherapy regimens. This groundbreaking advancement solidified the use of this therapy for patients diagnosed with unresectable MPM who had not previously undergone treatment.35

Subsequent to this milestone publication, the gates to immunotherapeutic interventions swung open in clinical practice, now reigning as the standard treatment approach for MPM patients, having secured approval from leading regulatory bodies such as the FDA and EMA.36–38 Despite the commendable progress achieved, the endurance of therapeutic response remains limited, and the recurrence rate of the disease remains high. Hence, there persists a need for dedicated research initiatives geared toward the dissection of mechanisms underlying immune therapy response, ultimately aiming to enhance treatment outcomes.

In summary, the advent of immune checkpoint inhibitors has heralded a transformative era in MPM treatment, breaking through the traditional boundaries to provide a promising avenue for patients with previously limited options.

Upon progression following first-line platinum-pemetrexed chemotherapy, there lacks a standardized therapy and scientific evidence remains limited. Second-line chemotherapy regimens involving vinorelbine, gemcitabine, or the gemcitabine-docetaxel combination, among others, have been evaluated in Phase II studies and retrospective analyses, yielding modest outcomes.39–44

The suboptimal results achieved within this context, coupled with chronic inflammation stemming from asbestos exposure as the main pathogenic factor7 and supported by the heightened expression of PD-L1 (20–60%),45,46 particularly in the non-epithelioid subtype, have spurred systematic investigation into immunotherapy as a second-line approach (Table 1).

The CTLA-4 inhibitor, Tremelimumab, was the pioneer immune checkpoint inhibitor studied in refractory MPM through non-randomized Phase II trials: the MESO-TREM 2008 trial47 and the MESO-TREM 2012 trial,16 each exploring different dosing schedules of the drug. Modest objective response rates (3–13%) were observed, but the survival outcomes were encouraging (median progression-free survival of 6.2 months and median overall survival of 11 months). However, Tremelimumab failed to significantly improve overall survival compared to placebo in the DERTERMINE study.48

The anti-PD-L1 antibody, Avelumab, demonstrated sustained antitumor activity in a basket-type Phase Ib study,49 particularly in a cohort of heavily pretreated mesothelioma patients. However, further clinical development in this pathology is still pending.

Nivolumab and pembrolizumab, both anti-PD-1 agents, boast the largest body of efficacy data in pre-treated MPM patients. Early efficacy and safety data with Pembrolizumab were gathered in the MPM cohort of the Phase Ib KEYNOTE-028 trial,50,51 enrolling 25 PD-L1-positive patients (≥1%, 22C3 IHC assay), achieving a 20% objective response rate and a median duration of response of 12 months. These results echoed previous Phase II findings from Desai et al.,52 where no patient selection based on PD-L1 status was performed. Furthermore, real-world data from Switzerland and Australia revealed similar efficacy outcomes for Pembrolizumab-treated patients with MPM progression,53 although with slightly inferior survival outcomes. Favorable outcomes were linked to elevated PD-L1 expression and non-epithelioid histologies.

Despite these encouraging results, the Phase III Pembrolizumab trial (ETOP-PROMISE-meso) did not meet its primary endpoint of progression-free survival. The study included 144 MPM patients progressing after platinum-based chemotherapy, with no PD-L1 selection, who were randomized 1:1 to receive either Pembrolizumab or chemotherapy (gemcitabine or vinorelbine as per investigator's choice). Progression-free survival was numerically inferior in the experimental arm (2.5 months vs. 3.4 months; HR 1.06; 95% CI 0.73 vs. 1.53; p=0.76), and there was no advantage in overall survival (10.7 months vs. 12.4 months; HR 1.12; 95% CI 0.74–1.79; p=0.59). Despite a 63% crossover rate, analysis adjusted for this factor failed to detect differences. However, the objective response rate was higher for the Pembrolizumab arm, aligning with previously discussed Phase II findings (ORR 22% vs. 6%). Exploratory analysis based on PD-L1 status (<1% or ≥1%, determined by E1L3N antibody) also failed to reveal differences in outcomes.54

Nivolumab in MPM progressing after chemotherapy has been evaluated both as monotherapy and in combination with anti-CTLA4. The German Phase II NivoMes trial enrolled 34 unselected PD-L1 population patients to assess efficacy and safety. The primary objective of disease control rate at 12 weeks was 47%, with an objective response rate of 26% and a median duration of response of 7 months. Survival data revealed median progression-free survival of 3.6 months and median overall survival of 11.8 months.55 Another similar study, the MERIT trial conducted in a Japanese population, yielded more favorable results with a disease control rate of 68% and extended survival medians (median progression-free survival of 6.1 months and median overall survival of 17.3 months). The objective response rate remained independent of histological subtype at 29%, while the sarcomatoid subtype demonstrated a remarkable 67% response rate.56

The French Phase II IFCT-1501 MAPS2 trial is a multicenter, randomized, non-comparative study evaluating nivolumab (n=63) or nivolumab–ipilimumab (n=62) as second-line treatment. The primary objective of disease control rate at 12 weeks was achieved at 44% and 50%, respectively. Other efficacy variables were consistent with previously reported nivolumab data and favored the combination arm (objective response rate 19% vs. 28%; median progression-free survival 4 months vs. 5.6 months; median overall survival 11.9 months vs. 15.9 months). Grade 3–4 toxicity was slightly higher in the combination arm.57 Another single-center Phase II study utilizing nivolumab–ipilimumab in second-line settings aligned with previously discussed results.58

The Phase III CONFIRM trial demonstrated the efficacy of Nivolumab compared to placebo. A total of 332 MPM patients who had progressed after first-line platinum-based chemotherapy, without PD-L1 selection, were randomized 2:1 to receive nivolumab or placebo. The study successfully met its co-primary endpoints with an absolute survival benefit of 3.3 months (median overall survival of 10.2 months vs. 6.9 months; HR 0.69) and a slight statistically significant increase in median progression-free survival (3.0 months vs. 1.8 months; HR 0.67). The objective response rate was 11% vs. 1% for placebo.59

An Italian-authored meta-analysis pooled evidence from 13 studies encompassing a total of 888 patients treated with anti-PD-L1/anti-PD-1 therapies. The overall response rate and disease control rate were 18.1% (95% CI: 13.9–22.8%) and 55.4% (95% CI: 48.1–62.5%), respectively. Median progression-free survival and overall survival demonstrated an increase from 2.1 months to 5.9 months and from 6.7 months to 20.9 months, respectively. The authors concluded that anti-PD-(L)1 ICIs can be considered a treatment option in MPM progressing after chemotherapy, even in the absence of identified predictive response factors.60

In conclusion, the landscape of treating MPM following failure of initial therapies has undergone a paradigm shift with the advent of immune checkpoint inhibitors. These agents have unlocked new possibilities for patients facing limited alternatives, ushering in a new era of hope and exploration.

The utilization of immunotherapy in the treatment of previously untreated MPM has been explored in numerous studies, both in monotherapy and in combination (Table 2).

One of the earliest pieces of evidence of clinical activity was reported in 2017 with the phase 1b KEYNOTE 028 study involving an anti-PD-1 agent, subsequently leading to investigations in the context of relapsed disease and later in the first-line treatment setting.51

While most current studies focus on CTLA-4 and PD-1 checkpoint inhibitors and their combinations, there are numerous other potential checkpoints that could be targeted in the future.

On one hand, mesothelin, a tumor antigen highly expressed in many tumors, including MPM and adenocarcinomas of the pancreas, ovaries, and lungs. It's an appealing therapeutic target due to its limited expression in mesothelial cells, which are dispensable. There are currently various therapeutic agents in clinical evaluation.74 Although most clinical trials with CAR T cells (NCT02414269, NCT04577326, NCT04489862) are in phase I or I/II, the results so far are promising, and all trials show manageable toxicity, although response rates have been low.75

Oncolytic viruses are emerging as targeted therapy for MPM due to their ability to destroy tumor cells without affecting non-tumor cells, releasing antigens that activate T cells through dendritic cells.76 In the case of MPM, therapy with adenoviruses,77 poxviruses,78 reoviruses,79 herpesviruses,80 and measles virus81 is being investigated. Virotherapy is one of the most promising alternatives, with various studies showing that human MPM cells are sensitive to many oncolytic viruses through direct cell death or immunomediated mechanisms. However, extensive research is still needed to define treatment alternatives more clearly.

WT1 (Wilms Tumor-1) is a highly overexpressed transcription factor in MPM that is widely used for diagnostic purposes. However, WT1 peptide antigens can trigger T cell responses in MPM cell lines.82 The adjuvant role of WT1 peptide analog vaccines within a multimodal treatment is being studied within multimodal treatment protocols, showing promising results with increases in both OS and EFS.83

Lastly, the role of microRNAs (miRNAs) must be highlighted. They posttranscriptionally regulate the expression of most protein-coding genes. In MPM, miRNA expression changes are characterized by global downregulation and are associated with the loss of tumor suppressor pathways. Although research on the role of different miRNAs is ongoing, for example, overexpression of miR-16 and miR34a, alone or in combination, slows cell cycle progression, modulates p53 and HMGB1 expression, and increases sensitivity to cisplatin, enhancing the drug's apoptotic effect.84 Furthermore, there are several phase I clinical trials with miR-16-5p,85,86 which have demonstrated safety and early signs of activity against MPM. Therefore, characterizing miRNAs in the future may offer an opportunity to identify different immune biomarkers that improve early diagnosis of this disease and provide novel therapeutic targets.

Malignant pleural mesothelioma remains a challenging neoplasm with a certain bad prognosis. As a rare malignancy, MPM's incidence, despite being relatively low, underscores the importance of understanding its pathogenesis, clinical course, and evolving therapeutic strategies.

The etiology of MPM is intricately linked to asbestos exposure, emphasizing the need for stringent occupational safety measures. Moreover, the nexus between asbestos exposure, lung cancer, and the synergistic impact of smoking mandates comprehensive public health interventions.

The advent of immune checkpoint inhibitors (ICIs) has ushered in a transformative era in MPM treatment. The landscape of ICIs in MPM, particularly focusing on PD-1 and CTLA-4 inhibition, has brought promising results in both monotherapy and combination approaches. Nivolumab, a PD-1 inhibitor, exhibited notable activity in MPM patients progressing after chemotherapy, with response rates varying across trials. The phase III CONFIRM study underscored nivolumab's efficacy by improving overall survival and progression-free survival compared to placebo. Additionally, combination strategies, like nivolumab–ipilimumab, have shown encouraging results, further highlighting the potential of dual immune checkpoint inhibition.

The complexity of MPM's molecular landscape, marked by specific gene alterations and pathways, has been illuminated by advances in high-throughput analyses. Genes like CDKN2A, NF2, and BAP1, along with their respective mutations, offer insights into the disease's biology and potentially serve as therapeutic targets.

In summary, MPM's formidable challenges persist, with limited treatment options and a historically grim prognosis. However, the emergence of immune checkpoint inhibitors has introduced a ray of hope, leading to unprecedented improvements in survival outcomes. While further investigations into predictive biomarkers and resistance mechanisms are essential, the rapidly evolving field of immunotherapy underscores its potential as a cornerstone in the management of MPM.

As we delve deeper into understanding MPM's molecular intricacies and harness the immune system's power, we stand at the cusp of a new era, one marked by personalized therapeutic strategies that promise to reshape the landscape of this formidable malignancy. As we continue to unravel its complexities, interdisciplinary collaboration and continued research efforts will be instrumental in offering a brighter future for MPM patients worldwide.

This review received no external funding.

All authors participated in the conception and design of the work. All authors believe that the manuscript represents valid work, have read it, and fully approved it.

The authors declare no conflict of interest related to this review.