Malignant pleural mesothelioma (MPM) is a fatal disease, mostly related to previous asbestos exposure (1). Its incidence is on the rise in the industrialized countries (2) and will reach its peak in the second to third decade of this century (3). The prognosis of MPM remains dismal because it is often diagnosed in an advanced stage of disease. Currently, an antifolate and platinum combination regimen represents the only established treatment for patients not amenable to curative surgery; however, this approach is largely unsatisfactory due to its limited impact on long-term survival of patients (4). Recently, a large randomized French study (MAPS) has shown that the addition of bevacizumab to cisplatin and pemetrexed results in an added benefit of 2.7 months in overall survival (OS) compared to standard therapy (5); however, this regimen is not yet considered a new standard of care in most countries. For patients who failed front-line chemotherapy the prognosis is even more dismal, as no standard second-line treatment has been yet defined (6). Among different therapeutic strategies largely investigated in MPM, immunotherapy represents a very promising approach (7). Indeed, spontaneous tumor-specific immune responses have been reported in MPM patients, and a better prognosis in patients with a high number of tumor-infiltrating immune cells has been demonstrated (8,9). In light of this evidence, a variety of clinical studies in the past explored the activity of different immunotherapeutic agents, in particular interferon- or interleukin-2-based regimens; unfortunately, these agents demonstrated limited efficacy or they were burdened with severe toxicity (10-13). A limited knowledge of multiple mechanisms of immune suppression operated by tumor cells, which include high levels of regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages in the tumor microenvironment, as well as non-appropriate methods for evaluating tumor response in the course of immunotherapy, could contribute, at least in part, to the failure of previous anti-tumor immunotherapeutic strategies (14).
In the recent years, a deeper understanding of the dynamic associations between pro-tumorigenic and anti-tumorigenic components of the MPM microenvironment and the interactions between tumor cells with host immune system have sparked new hopes to cure this disease with immunotherapy (15,16). Along this line, a number of immunotherapeutic clinical trials, aimed at activating the host’s immune system or overcoming components of the immunosuppressive tumor microenvironment, have been activated (17). Among these, the two main approaches of immunotherapy currently under investigation in MPM are focused on the targeting of immune-checkpoint inhibitors and mesothelin.
Immune checkpoint inhibitors
The remarkable progress in the clinical application of anti-tumor immunotherapy is mostly due to the development of therapeutic mAb (so-called immunomodulating mAb) targeting regulatory immune-checkpoints; these molecules are physiologically expressed on immune cells and play a crucial role in maintaining immune homeostasis and ensuring self-tolerance by mediating signals that attenuate excessive immune activation. Immunomodulating mAb restore and unleash anti-tumor activity of cytotoxic T cells by blocking inhibitor molecules on T cells or their ligand expressed on antigen presenting cells (APC) or tumor cells (18,19). This novel strategy has demonstrated its feasibility and efficacy in significantly prolonging long-term survival of patients with different malignancies in a large number of clinical studies, thus opening a new era in the history of cancer treatment.
Anti-cytotoxic T lymphocyte (CTLA)-4 mAb
CTLA-4 is a glycoprotein, member of the CD28 family receptors, inducibly expressed on the surface of activated CD4+ and CD8+ T cells, and constitutively expressed on regulatory T cells (19). CTLA-4 competes with CD28 costimulator receptor for the binding to ligand B7 (CD80 or CD86) expressed on APC; as CTLA-4 binds with higher affinity than CD28, it reduces CD28-dependent costimulation, and mediates direct inhibitory effects on the MHC-TCR pathway (19). Anti-CTLA-4 mAb by blocking CTLA-4 prevents its binding to B7, thus allowing T cells activation. Anti-CTLA-4 antibodies represent the prototype of this growing family of immunomodulating mAb targeting immune-checkpoints (19). Two anti-CTLA-4 mAbs are in clinical development: ipilimumab and tremelimumab. Ipilimumab represents the first of its class to demonstrate its ability to significantly improve the survival of metastatic melanoma patients (20), thus broadening its therapeutic exploration and prompting the clinical development of additional checkpoint blocking mAb in different tumor types, including malignant mesothelioma (MM) (21).
MESOT-TREM-2008 is the first study that explored the activity and safety of anti-CTLA-4 mAb in MM patients (22). In this phase II study, tremelimumab was administered at 15 mg/kg intravenous (IV) every 90 days in 29 second-line MM patients. Despite a low objective response rate (ORR) that was 7%, a long-lasting disease control and 2-year survival rate were observed in 31%, and 36% of MM patients, respectively (22). Additionally, grade 3–4 treatment-related side effects were observed in a minority of patients (22). These promising results were corroborated in the phase II MESOT-TREM-2012 study that investigated the activity and safety of tremelimumab in 29 additional second-line MM patients (23). In this second study, tremelimumab was given at an intensified dosing schedule of 10 mg/kg IV every 4 weeks (wks) for 6 doses, followed by administration of tremelimumab every 12 wks, based on previous pharmacokinetic data in metastatic melanoma patients (24). Four patients (14%) achieved an immune-related (ir)-ORR, thus the study reached its primary endpoint; among secondary endpoints explored, the ir-disease control rate (DCR) was 52%, the median duration of DCR was 10.9 months, and the median OS was 11.3 months; treatment was overall well tolerated, with grade 3–4 treatment-related toxicity observed in 7% of patients (23). These promising results contributed to the activation of a large, placebo controlled phase IIb study (DETERMINE); in this pivotal study tremelimumab was investigated in 571 second/third line MM patients at the same intensified schedule of administration utilized in the MESOT-TREM-2012 study (25). Unfortunately, the study did not show a superiority of tremelimumab for the primary endpoint of OS compared to placebo (25). Despite the failure of the study, this antibody class has had the merit of paving the way for the exploration of more effective immune checkpoint inhibitors, particularly those directed against programmed cell death protein (PD)-1 or its main ligand PD-L1 in this disease.
PD-1 is a trans-membrane inhibitory immune-receptor, member of the B7-CD28 family, expressed on activated T, B, and natural killer cells (26). It binds to PD-L1 or PD-L2 that are expressed on stromal and tumor cells; these interactions lead to a reduction of cytotoxic T cells, release of cytokines, proliferation, and finally to a depletion of T cells (26,27). Blocking PD-1 or PD-L1 by immunomodulating mAb, de-represses T cell activation, unleashing a clinical immune response towards the tumor (27). A growing number of anti-PD1/PD-L1 mAb has been recently approved in a variety of solid and hematological malignancies (28) thus prompting their investigation in additional tumor types including MPM.
The expression of PD-L1 has been reported in up to 60% of MPM samples in different series, with a higher rate in sarcomatoid histotype, and it has been associated to a poor prognosis (29-32). A growing number of phase I/II clinical studies with drugs targeting PD-1/PD-L1 axis are currently ongoing. In the phase Ib multi-cohort KEYNOTE-028 study, the anti-PD-1 pembrolizumab was investigated in PD-L1 positive pretreated MPM patients at a dose of 10 mg/kg every 2 wks (33). Five (20%) out 25 patients achieved a partial response (PR), and 13 (52%) a stable disease (SD); noteworthy, responses were durable with an average response duration of 12.0 months. Interestingly, the median progression free survival (PFS) was 5.4 months and the median OS was 18.0 months (33). The encouraging results observed in this first study prompted a rapid and large development of agents directed against the PD-1/PD-L1 axis in MPM. In a single-center phase II study, still ongoing at the University of Chicago (34), pembrolizumab was given in MPM and peritoneal MM patients at 200 mg every 3 wks; eligible patients were progressed to 1 or 2 prior regimens, and were unselected for PD-L1 status. Initial results reported an ORR of 21% and a DCR of 59%; median PFS was 6.2 months, and median OS was 11.9 months. Translational studies did not demonstrate a significant correlation between responses and PD-L1 expression or interferon-gamma gene expression profile (34). The activity of the anti-PD-1 nivolumab was investigated in the ongoing phase II NIVO-MES trial; 34 relapsed MPM patients received nivolumab at 3 mg/kg every 2 wks; preliminary data reported an ORR of 15%, regardless the PD-L1 expression on tumor cells, and a SD of 35%; median PFS was 3.6 months (35). In the phase II MERIT study, nivolumab was investigated at a flat dose of 240 mg IV every 2 wks in 34 second or third line MPM; results showed that 29.4% and 67.6% of patients reached an ORR and a DCR, respectively; in addition the PFS was 6.1 months and the median OS not reached at the time of that analysis (36). The role of nivolumab in pretreated MPM or peritoneal MM patients is currently being investigated in the randomized phase III double-blind, placebo-controlled CONFIRM study (37). In this study, patients progressed to at least two prior lines of chemotherapy are randomized in a 2:1 ratio to receive nivolumab at a flat dose of 240 mg or placebo. The trial has been recently opened in the United Kingdom, and will enroll 336 patients (37). In the phase Ib multicohort JAVELIN study, the anti-PD-L1 avelumab at the dose of 10 mg/kg every 2 wks was investigated in 53 MM patients progressing to at least one prior platinum/pemetrexed regimen (38). Patients were heavily pretreated, with a median of two prior treatments. A durable PR was observed in 5 (9%) patients; and an overall DCR was observed in 56% of patients. Median PFS was 17.1 wks, and the 24-week PFS was 38.4%. The most common treatment-related toxicity included fatigue, fever, infusion-related reactions, and dermatological side effects, similarly observed in trials with anti-PD-1 mAb (38).
Overall, these results indicate that targeting the PD-1/PD-L1 axis in MPM appears promising; however, these results have to be considered with caution because they are still very preliminary, and most of these trials are still ongoing. Therefore, several important issues regarding the role of these agents in MPM need to be further explored. Major efforts are currently directed to identify predictors of response to immune-checkpoint inhibitors, such as tumor molecular features or characterization of immune infiltrates in the tumor microenvironment, for a better patient selection for this therapeutic approach.
Combination strategy with immune-checkpoint blocking mAb
Though promising, the clinical benefit with PD-1/PD-L1 inhibitors is achieved by a limited proportion of MPM patients; to extend their benefit to a large population and to overcome primary or acquired immune-resistance observed in the majority of patients, current efforts are directed towards combined regimens.
Blocking of CTLA-4 could represent an optimal partner for combination regimen with PD-1/PD-L1 inhibitors; indeed these molecules act in two distinct phases of T cell activation; therefore, an additive or synergistic effect may be supposed by blocking these pathways. Consistently, evidence has shown a higher efficacy of nivolumab in combination with ipilimumab compared to nivolumab or ipilimumab alone in metastatic melanoma patients (39,40); along this line, a growing number of phase III clinical studies investigating the efficacy of combining CTLA-4 blockade with PD-1/PD-L1 blocking mAb are currently under investigation in different malignancies.
In the phase II NIBIT-MESO-1 study, the therapeutic potential activity of tremelimumab in combination with anti-PD-L1 mAb durvalumab was investigated in MPM and peritoneal MM patients (41). Forty patients received treatment with tremelimumab at a dose of 1 mg/Kg IV every 4 wks in combination with the anti-PD-L1 durvalumab at 20 mg/Kg IV every 4 wks for 4 doses during the induction phase, followed by durvalumab in monotherapy for additional 9 doses, in a maintenance phase. Primary endpoint of the study was to assess the ir-ORR in the study population; among secondary, were ir-DCR, ir-PFS, OS, and safety. The study is still ongoing but not recruiting. Safety analysis, was reported at ASCO meeting 2017, and demonstrated the tolerability of this combination regimen; indeed, most patients experienced mild or moderated ir toxicity (67.5%), and grade 3–4 treatment-related side effects were observed in 17.5% of patients; treatment-related toxicity was overall reversible according to protocol guidelines (41). Final efficacy analysis of NIBIT-MESO-1 study is currently ongoing.
In the phase II, randomized, non-comparative MAPS-2 study, nivolumab was investigated alone or in combination with ipilimumab in second or third line MPM patients. Final results have been recently shown at ASCO meeting 2017, and reported at week 12, a DCR of 44% or 50% with nivolumab alone or in combination with ipilimumab, respectively, thus the study reached its primary endpoint; among secondary endpoints explored, the median OS was 10.4 months with nivolumab alone, while it was not yet reached in the combo arm. Seventeen percent of patients experienced severe treatment-related side effects (42).
Several combination studies are currently ongoing, among these, the large, randomized, phase III Checkmate-743 study (NCT02899299) is currently investigating the efficacy of nivolumab in combination with ipilimumab in comparison to standard chemotherapy in first-line MPM patients; the Italian-Canadian phase III study is evaluating the efficacy of pembrolizumab alone or in combination with platinum-based regimen compared to chemotherapy alone in first-line MPM patients (NCT02784171). Additionally, a phase II study is exploring the immunological activity of durvalumab alone or in combination with tremelimumab in surgically resectable MPM (NCT02592551). Novel immune checkpoints are currently in early phase of clinical exploration in different tumor types; among these, in the phase I INDUCE-I study (NCT02723955), the safety and activity of GSK3359609 targeting the inducible T cell co-stimulator (ICOS), alone or in combination with pembrolizumab, is under investigation in selected advanced solid tumors including MPM. In Table 1 the main ongoing trials with immune checkpoints blockade utilized alone or in combination with different agents are reported.
Immune-targeting of mesothelin
Mesothelin is a cell-surface glycoprotein, highly expressed in many solid tumors, including mesothelioma, with limited expression in normal tissues (43); therefore, it represents an optimal therapeutic target. Along this line, a variety of compounds for targeting of mesothelin with different mechanism of action are currently at various phases of clinical development; they mostly include chimeric mAb amatuximab, recombinant immunotoxins (SS1P, RG7787/LMB-100), antibody-drug conjugates (such as anetumab ravtansine), and chimeric antigen receptor (CAR)-T cells (44).
- Amatuximab is a mouse-human chimeric anti-mesothelin mAb; in a phase II study, it was investigated in combination with cisplatin and pemetrexed in MPM patients with promising results in median OS that was 14.8 months (45); therefore a randomized, phase II trial was launched but prematurely closed due to low accrual (46).
- Anetumab-ravtansine is an antibody-drug conjugate; after its binding with mesothelin expressed on tumor cells, the antibody-drug conjugate is internalized and releases the cytotoxic agent ravtansine (47). In a small phase Ib study, anetumab-ravtansine showed a response rate in pretreated MPM patients of 50%, and a DCR of 90%; unfortunately, in the subsequent randomized phase II study (47), this compound failed to demonstrate an improvement in survival in comparison to vinorelbine in second-line MPM patients (48,49).
- Recombinant immunotoxins: SS1P (anti-mesothelin dsFv-PE38) consists of a murine anti-mesothelin disulfide-stabilized single-chain Fv fragment (targeting moiety) linked to PE38 (effector moiety), the protein-synthesis-inhibiting domain of Pseudomonas exotoxin A (50). In phase I studies, SS1P generated neutralizing antibodies to the pseudomonas endotoxin (PE) (51,52); therefore, in a subsequent study, pentostatin and cyclophosphamide were given before the administration of SS1P to deplete T and B lymphocyte, thus delaying the development of neutralizing antibodies; initial signs of activity were observed in 3/10 patients treated in a phase I study (53). To minimize immunogenicity, Hollevoet et al. re-engineered the targeting moiety from mouse dsFv to humanized Fab and de-immunized the effector moiety PE to generate a new immunotoxin, called RG7787/LMB-100 (54). A phase I study to assess the maximum tolerated dose and the immunogenicity of RG778 is currently under way in MPM patients (NCT02798536).
- Mesothelin CARs: adoptive T cell therapy using engineered T cells directed towards tumor antigens (CAR-T) is another promising approach that has shown impressive clinical outcomes in leukemia, and it is now being investigated in solid malignancies (55). Mesothelin is an especially appealing target for this approach since it is overexpressed in the majority of MPM, and several preclinical and clinical studies have found that is involved in tumorigenesis, as well as being associated with tumor aggressiveness (56). Data generated in CAR-T cells, mainly directed against mesothelin in MPM patients, demonstrated early signs of clinical activity and T cell reactivity towards the tumor. Mesothelin CARs are currently being investigated in multiple phase I clinical trials (NCT02414269, NCT01583686, NCT02580747, NCT02159716, and NCT01355965). Further adaptations of the CAR-T cell strategy, including intrapleural delivery approaches, are under investigation to increase tumor infiltration and decrease treatment-related side effects (57).
Other immunotherapeutic approaches
Additional immunotherapeutic strategies, including vaccines (such as CRS-207, a Listeria monocytogenes expressing human mesothelin), intrapleural administration of an adenovirus expressing interferon alpha (Ad.IFN-α), vaccination with a Wilms’ tumor-1 (WT-1) peptide analogue, dendritic cell vaccine, are currently under investigation in early phases of clinical studies (44). Table 1 reports the currently ongoing main trials, investigating the activity and safety of these therapeutic approaches.
Much has to be gained in the therapeutic scenario of MPM: the heterogeneity and the relatively low incidence of this disease, together with the difficult radiological evaluation of tumor response in MPM patients, particularly in the course of treatment with immunotherapeutic agents, pose barriers to developing more effective systemic therapies. However, in the last decade, a significant growth in the knowledge of mesothelioma immune-biology has translated into the development of a variety of novel immunotherapeutic agents that are beginning to show clinical potential in MPM patients. Targeting immune-checkpoint inhibitors and mesothelin, including combinations of these novel agents, appear to be among the most encouraging of the emerging therapeutic approaches.
Funding: This work was supported by unrestricted grants from Associazione Italiana per la Ricerca sul Cancro (IG15373, 2014).
Conflicts of Interest: L Calabrò served on Advisory Board of Bristol Myers Squibb; M Maio served on Advisory Boards of Bristol Myers Squibb, Roche-Genentech, AstraZeneca-MedImmune. The other author has no conflicts of interest to declare.
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