Mesothelioma is an insidious neoplasm arising from the mesothelial surfaces of the pleural and peritoneal cavities, the tunica vaginalis or the pericardium. Eighty percent of cases are of pleural origin. The incidence of malignant mesothelioma (MM) differs by gender and region, ranging from ten cases per million people (in the USA) to 29 cases per million people (in Australia and in the UK). It is more common among males (1,2).
The main risk factor for malignant pleural mesothelioma (MPM) is asbestos exposure, responsible for at least 80% of cases (3). In developed countries, the incidence of MPM is expected to peak in next decade, as there is a lag-time of 20–50 years after exposure, and regulation of asbestos was implemented in the 1970s and 1980s. Although smoking and asbestos exposure can multiplicatively increase the risk of developing lung cancer, smoking is not an independent risk factor (4).
Mesothelioma usually presents in the fifth to seventh decades of life. Typical symptoms are chest pain, dyspnea and weight loss (5). Clinically, distinguishing MPM from benign pleural effusions is challenging (6). Imaging investigations in suspected MPM can guide investigations, and the International Mesothelioma Interest Group now advises to diagnose epithelioid mesothelioma with cytological analysis on pleural fluid (7).
Patients with MPM have a very poor prognosis, with only a modest benefit conferred by modern therapeutics (8). Histological subtype is an important prognostic indicator, with progressively shorter survival in epithelioid MM, biphasic MM, and sarcomatoid MM (9).
A selected minority (<10%) of patients is eligible for a radical multi-modal treatment with a combination of systemic chemotherapy, surgery and/or radiotherapy (RT), in an effort to maintain locoregional tumour control after achieving a macroscopically complete resection. However, as of yet there is no standard of care for this so-called multimodality treatment (10). The 2018 British Thoracic Society (BTS) recommendations advise against extrapleural pneumonectomy in any way and against pleurectomy or decortication outside of clinical trials (11). Based on the results of the MAPS trial, they suggest the association of bevacizumab to a platinum-antifolate doublet to improve survival (12). Most patients have unresectable disease at diagnosis and a 12-month median overall survival with treatment. In these patients, doublet chemotherapies confer a 3-month median survival benefit (10).
Over the past decade, many therapeutic advances have been tested in MPM, including anti-angiogenic treatments and targeted therapies, with limited benefits (12). In this review, we will discuss the role of immunotherapy in MPM.
For the purpose of this review, we searched the term “pleural mesothelioma” on the publicly available clinical trials database (https://www.clinicaltrials.gov/). This yielded 187 results at the time of our search. We narrowed our focus to trials using immunotherapy. We excluded studies that were non-therapeutic, energy therapy focused (including radiation therapy), systemic chemotherapy focused, kinase inhibitor or other non-antibody inhibitor focused, and those designated as suspended, withdrawn, or with an unknown status.
Ultimately, 21 trials met our criteria; these trials have been categorized into two groups: immune checkpoint inhibitors (ICIs) and non-ICIs.
Furthermore, we performed a literature review on published data.
MPM tumor immune microenvironment
MPM is thought to stem from chronic inflammation following trapped asbestos fibres in the pleura.
A tumour microenvironment study found chronic stromal inflammatory response to be an independent predictor of survival (13). An investigation of immune responses in tumour and tumour-associated stroma in epithelioid MPM showed that high CD163+ tumour-associated macrophages and low CD8+ tumour infiltrating lymphocytes (TILs) were associated with poor prognosis, while low CD163+ tumour-associated macrophages and high CD20+ lymphocyte infiltration conferred an improved prognosis (14). Multiple studies have demonstrated the prognostic role of B cells, T cells and macrophages (14-17). Other investigators have published data showing the presence of immunosuppression in MPM through analysis of T-cell inhibitory receptors (18) and chemokines, such as C-C motif chemokine ligand 2 (CCL2), which is a factor in the protumour M2 macrophage recruitment (19). To tilt the immune microenvironment balance towards an anti-tumour immune response, several immunomodulatory agents are currently being investigated.
Under normal circumstances, tumour neoantigens elicit an immune response involving effector T cells and TILs. Tumour cells can adapt through the upregulation of cell surface inhibitory ligands. TILs express inhibitory receptors that bind to these ligands resulting in T-cell apoptosis and immune inhibition. These inhibitory receptors, also known as immune checkpoints, act as a regulatory system that prevent autoimmune reactions, but simultaneously play a crucial role in tumour development. Novel drugs known as ICIs are monoclonal antibodies (mAbs) able to interrupt inhibitory immune signals and to restore anti-tumour immune responses due to their interaction with checkpoint pathways such as cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death protein 1 (PD-1), and its ligand (PD-L1).
CTLA-4 is a glycoprotein expressed by activated T cells and regulatory T cells (Tregs), where it acts as an inhibitory regulator of the T cell mediated immune response; CTLA-4 competes with the co-stimulatory receptor CD-28 for B7 ligands (CD-80 and CD-86) expressed on antigen presenting cells (APCs). CTLA-4/CD-80 binding results in signalling that directly inhibits T-cell effector function. Consequently, mAbs that block the interaction of CTLA-4 with its ligands can enhance immune response including anti-tumour immunity. Two anti-CTL4 are currently available, ipilimumab and tremelimumab.
Ipilimumab, an IgG1 monoclonal antibody, was the first ICI to demonstrate a survival benefit. After initial studies in melanoma, it was investigated alone and in combination with PD1 blockade in numerous cancers. In MPM, it has mainly been evaluated in combination with PD1 blockade, and we will discuss its efficacy alongside that of PD1 inhibitors.
Tremelimumab, a selective human IgG2 anti-CTLA-4 monoclonal antibody, showed efficacy in two small phase 2 studies called MESOT-TREM-2008 and MESOT-TREM-2012 and in April 2015, it received orphan drug designation by the US Food and Drug Administration (FDA) to treat MPM (20,21). MESOT-TREM-2008 is a phase 2 study, evaluating tremelimumab in second-line MPM patients. Despite a 7% objective response rate (ORR), the disease control rate (DCR) and 2-year survival rate were 31%, and 36%, respectively (20). These promising results were corroborated in the phase II MESOT-TREM-2012 in 29 additional second-line MPM patients (21). In this second study, tremelimumab was given at an intensified dosing schedule of 10 mg/kg IV every 4 weeks for 6 doses, followed by administration of tremelimumab every 12 weeks, based on previous pharmacokinetic data in metastatic melanoma patients (22). There was a 14% ORR, a 52% DCR with a 10.9-month median duration of response and 11.3-month OS. Grade 3–4 treatment-related toxicity was observed in 7% of patients.
On this basis, Maio et al. conducted the DETERMINE trial, a large phase 2b randomized placebo-controlled study of tremelimumab administered in 571 pretreated patients with pleural (95%) or peritoneal mesothelioma with the same treatment schedule as in MESOT-TREM-2012 (23). However, no OS nor DCR benefit was found. Thus, single agent anti-CTLA4 therapy cannot be recommended in MPM.
PD-1 is a transmembrane inhibitory immune receptor, expressed on activated T, B, and natural killer cells (24). It binds to PD-L1 or PD-L2 that are expressed on stromal and tumour cells. These interactions lead to T-cell exhaustion, with reduced cytokine release, cellular proliferation, and ultimately cause apoptosis. Blocking PD-1 or PD-L1 by immunomodulating mAb, reinvigorates T cell activation, unleashing an immune response towards the tumour (25). PD-L1 expression is found in up to 60% of MPM samples, with a higher rate in the sarcomatoid histotype, and is associated with poor prognosis. The median overall survival in PD-L1 expressing advanced mesothelioma is 5 months, while it is 14.5 months in PD-L1 negative mesothelioma (26-29).
Nivolumab, a fully humanized anti-PD1 mAb, has been investigated in multiple MPM trials. The NIVOMES trial is a single arm, phase 2 trial in 34 previously treated patients with MPM. Patients received nivolumab 3 mg/kg every two weeks. At three months, there was a 24% ORR and 47% DCR. The results were not correlated to PD-L1 expression. Grade 3–4 adverse events occurred in 26% of patients (30). These results were echoed by the phase 2 MERIT study, investigating nivolumab at a flat dose of 240 mg IV every 2 weeks in 34 second or third line MPM. There was a 29.4% ORR and 67.6% DCR, and the PFS was 6.1 months, while the median OS was not reached at the time of that analysis (31).
The aptly named CONFIRM trial is an ongoing phase 3 double-blind, placebo-controlled study aiming to confirm the benefit of nivolumab in pre-treated mesothelioma patients. In this study, patients who progressed after at least two prior lines of chemotherapy are randomized to nivolumab at a flat dose of 240 mg or placebo. The trial recently opened in the United Kingdom, and will enrol 336 patients (32).
Pembrolizumab is another anti PD-1 mAb that has been investigated in MPM. In the phase 1B multi—cohort Keynote 028 study in pre-treated MPM, pembrolizumab was administered at 10 mg/kg every 2 weeks in 25 MPM patients. 20% achieved a PR, 52% a SD, and the median DOR was 1 year. Interestingly, the median PFS was 5.4 months while the median OS was 18.0 months (33). These encouraging results led to multiple pembrolizumab trials in MPM.
In a phase 2 trial in previously treated pleural or peritoneal mesothelioma, three-weekly 200mg pembrolizumab was administered to 65 mesothelioma patients (86% pleural, 14% peritoneal). In the MPM cohort, the ORR was 20%; interestingly, with a 40% ORR in sarcomatoid subtypes. Median PFS was 4.5 months and OS 11.5 months. Grade 3–5 toxicity occurred in nearly 20% of patients. There was a trend toward higher ORR and PFS with PD-L1 expression (34).
A large multicentre randomized phase 3 ETOP trial, PROMISE-meso, is ongoing. It has included 144 pre-treated MPM patients and is comparing pembrolizumab to standard chemotherapy. Pembrolizumab is administrated at 200 mg fixed dose every 3 weeks (35). This should provide more accurate answers to the benefit of pembrolizumab. A similar large phase 2/3 randomized 3 arm trial is comparing pembrolizumab to standard chemotherapy and to the combination thereof (36).
Pemrolizumab is also being evaluated in the neoadjuvant setting for resectable MPM patients in a single-arm phase 1 trial. Patients will receive three cycle of flat dose 200 mg pembrolizumab, followed by surgical resection and adjuvant platinum-pemetrexed chemotherapy (37).
In parallel, there are multiple trials studying the addition of pembrolizumab to other types of treatments. A phase 1 trial is evaluating the safety and efficacy of the addition of pembrolizumab and image-guided resection to surgery and chemotherapy for MPM (38).
Another small phase 1 safety trial is testing adjuvant pembrolizumab after radiation therapy for lung-intact MPM in pre-treated patients (39).
PD-L1 blockade works by targeting the tumoral ligand rather than the receptor on T cells, with the same biological rationale as PD-1 inhibition. The phase 1b JAVELIN trial evaluated avelumab, an anti-PD-L1 antibody, in 53 MPM patients who progressed after a platinum-pemetrexed regimen. The ORR was 9% (5 patients), yet disease control rate was 58% and median duration of response was 15.2 months. The ORR was higher in PD-L1-positive tumours (19%) than negative tumours (7%). The most common treatment related toxicity included fatigue, fever, infusion-related reactions, and dermatological side effects and there were 9% Grade 3–4 adverse events. Further studies are warranted for this drug (40).
Different studies are currently ongoing to evaluate another anti-PD-L1 antibody, atezolimumab. A large randomized phase 3 trial is comparing atezolizumab plus bevacizumab and chemotherapy versus bevacizumab and chemotherapy as first-line treatment for advanced MPM (41). Other smaller trials are investigating single-agent atezolizumab post-chemotherapy in MPM, as well as a neoadjuvant study evaluating combined chemo-immunotherapy (42,43).
The single-arm, phase 2, DREAM trial is investigating the combination of the anti-PD-L1 mAb, durvalumab, with first line chemotherapy in MPM. Preliminary results among 54 patients showed an impressive 61% ORR and 71% 6-month PFS rate. However, 57% experienced Grade 3 or greater adverse events (44).
Combination PD-1 and CTLA-4 blockade
The failure of single agent tremelimumab after promising early results led to combination ICI trials in mesothelioma. Tremelimumab was combined with durvalumab, an anti PD-L1 monoclonal antibody in a single-arm phase 2 trial on 40 unresectable mesothelioma patients. There was a 28% ORR, with a median response duration of 16.1 months and a median overall survival of 16.6 months. PD-L1 expression was not predictive of response. 18% of patients had Grade 3–4 treatment-related adverse events (45).
The same combination is under investigation as neoadjuvant therapy. The treatment is administered one to six weeks prior to resection. The primary outcomes are the intratumoral ratio of CD8 T cells to Tregs (CD8/Treg), the percentage of inducible T-cell co-stimulator (ICOS), CD4 T cells and PD-L1 expression (46).
The combination of nivolumab and anti-CTLA4, ipilimumab, has proven its efficacy in melanoma and kidney cancer and is currently under investigation in multiple cancers including mesothelioma. INITIATE, a single arm phase 2 trial of nivolumab and ipilimumab in 34 patients with MPM showed promising results, with 29% PR, a 68% DCR but 34% Grade 3 toxicity (47). Subsequently, the randomized, non-comparative IFCT-1501 MAPS2 evaluated the efficacy and safety of nivolumab and ipilimumab with nivolumab in 125 pre-treated MPM patients. Nivolumab was administered at 3 mg/kg every 2 weeks and in the combination group, ipilimumab was added at 1 mg/kg every 6 weeks. The primary outcome was 3-month DCR. In the intention-to-treat population, the 3-month DCR was 40% versus 52% in the monotherapy versus combination groups, respectively. Grade 3–4 adverse events occurred in 14% of nivolumab patients and 26% of combination therapy patients, and the latter group also has 3 treatment related deaths. Positive tumour PD-L1 expression (with a cut off of 1%) was associated with increased objective response or disease control in both groups. However, positive PD-L1 tumour expression only led to longer OS in the nivolumab group (48).
This trial thus confirms the results from the other smaller anti PD-L1 trials showing that anti PD- 1 or anti PD-L1 antibodies have activity in patients with MPM. Larger clinical trials are needed to determine whether the combination is better than single agent PD-1 blockade.
Given the efficacy of ICI in subsequent lines of therapy, nivolumab combined with ipilimumab is currently being evaluated in first-line in a randomized phase 3 trial, Checkmate 743, versus standard first line platinum-pemetrexed chemotherapy in MPM (49).
Non-checkpoint inhibitor immunotherapy: T cell mediated treatments
Innovative cellular therapies are currently under investigation to control MPM, as shown by ongoing clinical trials. These include novel techniques to reactivate the immune. Adoptive cell transfer (ACT) is a type of immunotherapy that entails the collection of the host’s immune cells from peripheral blood or the tumour itself, followed by isolation, modification, and ex vivo expansion of the targeted immune cells. The modified immune cells are then reinfused into the patient as therapy (50). ACT offers the advantage of targeting effector cells to a specific tumour-associated antigen and leads to direct cytotoxicity. Two of the major categories of ACT are chimeric antigen receptor (CAR) T-cells and TIL infusions.
One approach is to use CARs in order to create a cancer-specific antigen receptor and couple this to effector cells, such as T cells (51). A CAR construct consists of an extracellular antigen-binding domain that is hinged to one or more intracellular signalling domains (52). Once constructed, the CAR is then transduced into autologous T cells and reinjected to the patient as therapy. CARs have been used in acute lymphoblastic leukemia in children with spectacular responses leading to the fast development of this strategy (51). CAR T-cells can have different targets based on antibody and co-stimulatory domains. Mesothelin is a cell-surface glycoprotein over-expressed in up to 95% of patients with epithelioid MPM, though not in the 10–15% of sarcomatoid histotypes (53). It is also be over-expressed in other tumour types. As mesothelin has limited expression in normal tissue, it is a promising cancer-associated antigen target. Furthermore, several preclinical and clinical studies have found that is involved in tumorigenesis, as well as being associated with tumour aggressiveness (54). In preclinical studies, CARs specific against mesothelin were able to decrease tumour size after injection (55). Responses have been mixed, perhaps due to the loss of expression of the targeted antigens (56).
Ongoing phase 1 trials of CAR T-cells in MPM have different designs (Table 1) (57-62). In a phase 1 trial, lentiviral transduced mesothelin targeting CAR T-cells are being administered intravenously with or without cyclophosphamide in mesothelin-expressing tumours including metastatic pancreatic cancer, serous epithelial ovarian cancer and MPM (61). Two further phase 1/2 trials are ongoing with intravenous anti-mesothelin CAR T-cells (60,62).
Similarly, mesothelin targeting CAR T-cells are being investigated with intra-pleural infusions in malignant pleural disease arising from lung cancer, breast cancer or MPM. This trial has an additional arm including pembrolizumab, with promising early results with a response in eight out of 11 patients (59).
The second ADT immunotherapeutic strategy we will discuss is the infusion of autologous TILs. TIL therapy initially showed promising efficacy in the treatment of malignant melanoma but its application to other malignancies has presented several challenges. The extraction of sparse tumour-reactive lymphocytes and subsequent isolation and expansion of T-cells that retain specificity and functionality can be challenging (52). Additionally, prolonged clinical response to TIL therapy requires lymphodepletion, with the significant infectious risks it entails (50).
In MPM, there is currently a phase 1/2 trial investigating the safety and efficacy of intravenous autologous TILs after lymphodepletion by cyclophosphamide and fludarabine. After the infusion, patients receive two weeks of low-dose interleukin-2 therapy to promote continued TIL proliferation and activity (63).
Another approach is cancer vaccination. It has been developed by the discovery of tumour associated antigens and involves activating a specific immune response after stimulation through the vaccine. After vaccination, autologous dendritic cells are capable of capturing and processing tumour antigens and express co-stimulatory molecules such as cytokines that will enhance the immune response. Some studies have shown that MPM express high levels of WT1, a protein that regulates gene expression in cancer cells (64). One study is currently recruiting patients to evaluate the effect of a WT1 vaccine associated with platinum-based chemotherapy in front-line treatment in MPM.
Thus, novel ADT strategies appear promising from a scientific perspective, and results of these trials are eagerly awaited, as they could dramatically change the treatment landscape for refractory MPM.
There are currently 21 ongiong trials for MPM evaluating immunotherapy, illustrating the high hopes for these treatments (Table 1).
Though MPM is a rare cancer, its incidence is expected to peak in next decade. Therefore, given the limited current therapeutic options, identifying safe and effective treatments for this disease is a worthwhile challenge. Immunotherapy, including but not limited to checkpoint inhibition, is a promising and rapidly developing treatment approach.
The role of front-line combination doublet chemotherapy is well established and the benefit of adding an ICI remains to be proven. Similarly, current results do not warrant the use of first-line ICI monotherapy, though large trials are ongoing.
As there is no second-line standard of care, it is tempting to give ICI in this context based on phase 1/2 results. Given current data, single agent anti CTLA-4 therapy is not recommended. On the contrary, PD-1 blockade, as well as combination therapy, are very promising.
Although preliminary data from early studies are encouraging, caution should be exercised, as such results often fail to translate clinical benefit in phase 3 trials. Should these trials confirm their efficacy, the challenge will be analogous to that currently faced in lung cancer: the identification of predictive biomarkers, the choice of ICI and the role and timing of combination therapies. Furthermore, the potential role of CAR T-cells and autologous TIL infusions in MPM will soon be elucidated. Finally, this will have to be integrated with the use other treatment modalities in order to offer the best possible care for mesothelioma patients.
Conflicts of Interest: The authors have no conflicts of interest to declare.
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Cite this article as: Colarusso G, Terzic J, Achard V, Friedlaender A. The role of immunotherapy in mesothelioma. Precis Cancer Med 2019;2:21.