Mesothelin: An Immunotherapeutic Target beyond Solid Tumors

6.1. Immunotoxins and Monoclonal Antibodies

SS1P is an anti-mesothelin immunotoxin, an antibody-based therapy with a bacterial toxin payload. This recombinant protein consists of a murine Fv fragment linked to a Pseudomonas exotoxin A payload [ 70 ]. Although the toxin was well tolerated and exhibited significant anti-tumor activity [ 59 ], the efficacy was limited by the development of neutralizing antibodies. This limitation was overcome by combining SS1P with chemotherapy agents that suppress the host immune system [ 71 ]. LMB-100 is a second-generation immunotoxin comprising a humanized anti-mesothelin fragment and a modified Pseudomonas exotoxin A payload which was designed to be less immunogenic [ 72 ]. LMB-100 has been similarly limited by the development of anti-drug antibodies [ 73 , 74 ]. In mesothelioma, the combination of LMB100 and anti-PD-1 antibody therapy has enhanced efficacy comparative to solo therapies [ 75 ]. Both modalities continue to be studied in combination with chemotherapy in mesothelin-expressing solid tumors.

Amatuximab (originally called MORAb-009) is a monoclonal antibody which targets mesothelin, thereby disrupting cell adhesion and initiating antibody-dependent cytotoxicity [ 76 ]. The anti-tumor effect and maximum tolerated dose have been established in completed phase I and II clinical trials in combination with chemotherapy [ 77 , 78 ]. In vitro studies indicate that amatuximab inhibits mesothelin interaction with CA125/MUC16 and such a blockage reduces the cancer’s ability to metastasize and invade into other tissues. Additionally, amatuximab treatment downregulated cancer stem cell markers, such as CD44, c-MET, and ALDH1 in pancreatic cancer cells [ 79 ]. Amatuximab treatment increased sensitivity to gemcitabine and reduced the expression of c-Met and AKT in the liver, accompanied by decreased rates of pancreatic cancer cell metastasis [ 79 , 80 ].

6.2. Vaccines

GVAX is a granulocyte–macrophage colony-stimulating factor (GM-CSF) tumor cell vaccine which expresses multiple antigens and induces anti-tumor immune responses by cross-priming mechanisms to recruit antigen-presenting cells [ 81 ]. Mesothelin was identified as a target of T cells in patients treated with GVAX, initiating the development of a Listeria monocytogenes vaccine (CRS-207), which expresses tumor-associated antigen mesothelin. CRS-207 secretes mesothelin in the cytosol of infected antigen-presenting cells, which is processed and presented by major histocompatibility complex (MHC), thereby stimulating an immune response [ 82 , 83 ]. A phase II study using CRS-207 in combination with GVAX and conventional chemotherapy for patients with previously treated metastatic pancreatic adenocarcinoma improved overall survival [ 84 ]; however, a follow-up phase IIb study showed similar survival as chemotherapy [ 85 ]. A phase I study of CRS-207 in addition to conventional chemotherapy for the treatment of patients with malignant pleural mesothelioma found that it was well tolerated, with few adverse events. They reported reduced tumor sizes and an improvement in survival, including one complete response [ 86 ].

6.3. Antibody–Drug Conjugates

Anetumab ravtansine is an antibody–drug conjugate (ADC) comprised of a humanized anti-mesothelin antibody conjugated to DM4 (a maytansinoid tubulin inhibitor), which showed potent killing of tumor cells expressing mesothelin [ 87 ]. The drug binds specifically to mesothelin-expressing tumor cells and releases its cytotoxic payload following internalization. Phase I trials in patients with advanced solid tumors suggested that anetumab ravtansine can be safely given to patients and supported its anti-tumor efficacy [ 88 ]. Additional phase I and II trials are ongoing. Preclinical studies showed an improved anti-tumor effect when used in combination with standard chemotherapy in ovarian cancer models [ 89 ].

ADC DMOT4039A, a humanized anti-mesothelin monoclonal antibody conjugated to monomethyl auristatin E (MMAE), which has anti-mitotic effects, was found to be safe in a phase I clinical trial [ 90 ].

Another immunoconjugate, BMS-986148, conjugated to tubulysin, which disrupts microtubule assembly and induced apoptosis, was evaluated in solid tumors. Phase 1/2a studies of BMS-986148 treatment alone or in combination to nivolumab, a PD-1 inhibitor, was concluded to have manageable safety as well as clinical activities, warranting further clinical trials in combination with other checkpoint inhibitors [ 91 ].

6.4. Chimeric Antigen Receptor T Cells and T Cell Receptor Fusion Constructs

Chimeric Antigen Receptor (CAR) T cells are autologous patient T cells which are genetically modified to target a cancer-specific protein. When these cells bind to their target, they become activated, proliferate and mediate cytotoxic effects [ 92 ]. CAR-meso T cells consist of an anti-mesothelin scFv fused to TCRzeta signaling and costimulatory domains, allowing for specific binding to mesothelin expressing cells and subsequent cytotoxic response [ 93 , 94 ]. Preclinical studies of mesothelin targeting CAR-T cells have shown significant tumor reduction and are currently under clinical evaluation by many groups [ 93 , 95 ]. Phase I studies have shown that mesothelin targeting CAR-T cells are well tolerated with minimal on-target off-tumor effects but showed limited clinical activity [ 65 ]. There are many ongoing trials investigating mesothelin-directed CAR-T cells in solid tumors [ 96 ].

Most recently, novel T cell engineering platforms which target mesothelin have been investigated. T cell receptor fusion constructs (TRuCs) target tumor cells independent of MHC, resulting in increased T cell activation. Preclinical studies with mesothelin-directed TRuCs have shown robust anti-tumor activity, with faster rates of accumulation in mesothelin-expressing tumors, lower levels of cytokines, increased levels of chemokine receptors, and long-term functional persistence [ 97 ].

CAR-T Cell Alterations

CAR-T cells are conventionally designed against single antigens of interest; however, Tandem CAR-T cells targeting two antigens may be more effective and have higher anti-tumor effects than single antigen targeting CAR-Ts. These Tandem CAR-Ts allow for simple Boolean logic gates of “AND”, “OR”, or “NOT”, as they can recognize multiple antigens, and have been used in hematological malignancies, including acute lymphoblastic leukemia to simultaneously target CD19 and CD20 [ 98 , 99 ]. Tandem CAR-Ts targeting cancer-specific upregulated molecules mesothelin and folate receptor 1 (FOLR1) with secretory activity of IL-12 had higher infiltration and persistence comparative to anti-mesothelin CAR-Ts, and the secretion of IL-12 enhanced therapeutic effects and reduced tumor antigen escape in ovarian cancer [ 100 ]. These data suggest that the identification of multiple tumor-associated antigens would improve the results of CAR-T cells by applying Boolean logic for the recognition of multiple targets to reduce antigen escape.

The silencing of PD-1 on CAR-T cells with the use of shRNA resulted in increased efficacy and an enhanced anti-tumor effect on several mesothelin-expressing cancers [ 101 ]. The success of PD-1 silencing in CAR-T cell therapy opens the door to the gene silencing or activation of other genes in these cells to improve anti-tumor effects. Another antigen of interest with CAR-T cells is Tim3 (T cell immunoglobulin domain and mucin domain 3), which is an immune checkpoint receptor that helps regulate T cell response in the tumor microenvironment. Tim3 plays a role in immunosuppression and T cell death. Blocking Tim3 function reduced immunosuppression, reduced regulatory T cells, and increased IFN-γ production from T cells [ 102 , 103 ]. Blocking Tim3 expression on mesothelin CAR-T cells through shRNA had improved cytotoxicity effects, increased cytokine production, and higher proliferation capacity compared to their Tim3+ counterparts [ 104 ]. These two studies present the possibility of customizing CAR-T cells to overcome mechanisms that inhibit their function within the tumor microenvironment and will need further investigation to identify and silence other immunosuppressive targets.

Another factor that decreases the efficacy of CAR-T cells is the production of adenosine in the tumor microenvironment. The overproduction of adenosine from tumor cells facilitates immunosuppression through the binding of the adenosine 2a receptor (A2aR). The knockdown of A2aR through shRNA in CAR-T cells increased the anti-tumor ability of the CAR-T cells both in vivo and in vitro. In xenograft models, the A2aR-disrupted anti-mesothelin CAR-T cells decreased the tumor burden compared to unmodified T cells and anti-mesothelin CAR-T cells [ 105 ]. Expression of anti-mesothelin CAR-T cells with cell chemokine receptors CCR2b and CCR4 revealed enhanced migration of CAR-Ts in vitro and displayed high levels of cytotoxicity and increased levels of IL-2, IFN-γ, and TNF-α, revealing CCR2b as the superior chemokine receptor in NSCLC in vivo studies [ 106 ].

6.5. Chimeric Antigen Receptor Natural Killer Cells

Similar to CAR-T cells, natural killer (NK) cells can also express chimeric antigen receptors and are possibly more effective than CAR-T cells due to their increased ability to recognize and kill tumor cells to result in tumor-specific killing. In a study on ovarian cancer, CAR-NK cells were designed to recognize mesothelin, and were effective in eliminating mesothelin+ cancer cells through increased cytokine secretion compared to the parental NK cell treatment [ 107 ]. In an in vitro study using anti-mesothelin NK cells against gastric cancer, mesothelin-NK cells were more selective in killing mesothelin+ tumors and secreting cytokines comparative to transduced NK cells and were able to prolong survival rates of patient-derived xenograft (PDX) mice in vivo [ 108 ].

6.6. Bispecific T Cell-Engaging Molecules

Bispecific T cell engagers (BiTEs) are small fusion proteins consisting of two single chain variable fragments (scFvs): one which targets an effector cell (most commonly CD3 on T cells) and another which targets the tumor antigen. These bispecific antibodies redirect the cytotoxic effects of T cells toward specific tumor cells [ 109 ]. While the use of BiTEs has been most notable in hematologic malignancies and B cell acute leukemias in particular, they have been developed for a number of different tumor antigens. Research into the use of BiTEs which target mesothelin are currently underway in triple-negative breast cancer, pancreatic ductal adenocarcinoma, lung cancer, and other solid tumors [ 110 , 111 ].

One drawback to using BiTEs in vivo is their short half-life of a few hours, thereby requiring administration via intravenous infusions. To overcome this limitation, Suurs et al. designed an anti-mesothelin/anti-CD3 BiTE that also had an Fc-domain that increased the half-life and required only intermittent dosing of BiTEs. PET imaging in BALB/c mice revealed the tumor-tissue specific uptake of the BiTE molecule and a half-life of about 63 h [ 112 ]. A similar bispecific antibody in the IgG format with bivalency for mesothelin in addition to binding CD3 showed higher efficacy than a corresponding antibody with monovalent mesothelin binding capacity [ 113 ]. A trispecific T cell-activating construct, HPN536, has been used to treat mesothelin-expressing solid tumors. In addition to binding to CD3 and mesothelin, HPN536 binds serum albumin to increase the plasma half-life of the molecule. In in vivo studies of cynomolgus monkeys, HPN536 was well tolerated and exhibited mesothelin-dependent pharmacokinetics, which led to a phase I clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT03872206","term_id":"NCT03872206"}} NCT03872206 ) using HPN536 against solid tumors [ 114 ].

6.7. Targeted Alpha Therapies

Targeted alpha therapies (TAT) represent a new emerging class of targeted cancer therapies that use high-energy emissions from alpha particles to elicit permanent double-stranded breaks in DNA, ultimately resulting in cell death [ 115 ]. Targeted thorium-227 conjugates (TTC) represent a subtype of TATs that consist of a covalently attached 3,2-HOPO chelator to a specified antibody to ensure the delivery of thorium-227, an alpha particle emitter, to mesothelin-expressing cells. The specific mesothelin TTC, BAY 2287411 in mesothelioma, ovarian, and breast cancers, among others, showed anti-tumor potency both in vitro and in vivo in PDX models. The cellular response of BAY 2287411 included increased DNA double-stranded breaks, oxidative stress, and apoptotic markers. The results from this study support the transition of BAY 2287411 to a phase I clinical trial to treat ovarian and mesothelioma cancers [ 67 ]. A combination therapy of BAY 2287411 with DNA damage response inhibitors results in a synergistic effect by sensitizing the cells to DNA damage [ 116 ]. Targeted alpha therapies remain as one of the least investigated targeted therapeutic options when treating mesothelin-positive tumors.

6.8. Impact of Mesothelin Shedding on Mesothelin-Targeting Therapies

As previously noted, many GPI-anchored proteins undergo routine extracellular shedding, to which mesothelin is no exception. Shed mesothelin could decrease the efficacy of targeted therapies, resulting in an on-target, off-tumor response of the drugs interacting with soluble mesothelin. The most notable sheddase involved in mesothelin shedding is TACE/ADAM17; however, many members of the ADAM, MMP, and BACE protease families are able to shed mesothelin from the cell surface. Inhibiting the shedding of mesothelin with drugs that limit functionality of sheddases has shown promising results in vitro by increasing drug efficacy and cell surface mesothelin [ 16 , 61 ]. The identification of an epitope on the fragmented mesothelin that remains unshed on the surface of the membrane would be more effective in targeting mesothelin.

7. Role of Mesothelin in Hematological Malignancies

The overexpression of mesothelin has been well described in several solid tumors; however, there are limited data regarding its expression in hematologic malignancies. Mesothelin expression was lacking in all 442 tissue microarray specimens, representing different types of lymphoma. This study did not evaluate samples from other hematological malignancies [ 41 ]. In 2006, Steinbach et al. identified MSLN as one of the seven genes overexpressed in pediatric AML compared to normal bone marrow [ 117 ]. Further investigation detected mesothelin protein expression in a small number of primary pediatric AML samples [ 118 ]. Recently, massive sequencing efforts in pediatric AML under the direction of Children’s oncology group and NCI (TARGET initiative) identified mesothelin to be expressed in greater than a third (36%) of AML samples [ 11 ]. Mesothelin expression was quantified and subsequently confirmed using quantitative RT-PCR and flow cytometry. Data from TCGA and BEAT databases showed that only about 14% of adult AML samples expressed mesothelin. Among the various cytogenetic subtypes of pediatric AML, core binding factor AML (comprising inv(16), t(8;21)), and KMT2A rearranged AML comprised 49% and 40% of samples with mesothelin positivity, respectively.

How mesothelin expression is triggered in AML is not known. In pediatric AML patients, genomic characterization revealed that mesothelin expression is inversely correlated with MSLN promoter hypermethylation, consistent with previously described data from solid tumor studies. AML samples with high promoter methylation were characterized as low mesothelin expressers via flow cytometry [ 11 ].

Preclinical studies to evaluate the efficacy of mesothelin-targeted therapies such as immunotoxin, ADC, BiTEs, CAR-T cells, and CAR-NK cells in pediatric AML have been conducted ( Figure 3 ). An early study using recombinant anti-mesothelin immunotoxin SS1(dsFv)PE38 in vitro failed to produce a cytotoxic effect. The authors speculated that other mesothelin-targeted approaches could be more beneficial [ 118 ]. Accordingly, both in vitro and in vivo evaluations of ADC anteumab ravtansine in AML samples resulted in the selective killing of mesothelin-expressing cell lines. Mice xenografted with mesothelin+ samples survived longer when treated with the ADC compared to the isotype drug conjugate control and mesothelin-negative samples exposed to either treatment. Another MSLN-ADC, DGN462, bearing a DNA alkylating agent, also showed preclinical efficacy in pediatric AML [ 11 ]. The combination of the ADC treatment with traditional chemotherapy regimen of daunorubicin and cytarabine led to higher survival rates compared to any treatment alone, suggesting a synergistic effect [ 119 ]. A phase I clinical trial for anetumab ravtansine is currently under development by the Children’s Oncology Group for mesothelin+ pediatric AML patients in second relapse [ 120 ].

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Figure 3

Mesothelin-targeted therapies in preclinical development for pediatric AML. Anetumab ravtansine is an antibody–drug conjugate (ADC) that is an scFv for mesothelin attached to DM4 (red star), a tubulin inhibitor, via a linker (yellow). Once bound to mesothelin, DM4 is internalized and binds to tubulin, which disrupts microtubule assembly and cell cycle is inhibited, which results in cell death. Chimeric antigen receptor (CAR) therapy uses a variety of host immune cells to elicit a tumor-targeted response using a construct designed to recognize a target antigen. In AML, CAR-NK cells (yellow), and CAR T cells (orange) have been investigated. Upon the recognition of the target antigen, NK and T cells activate and elicit a killing mechanism through the secretion of perforin and granzymes (blue), resulting in tumor cell lysis. Bispecific T cell-engaging molecules (BiTEs) work mechanistically by recruiting T cells to tumor cells by engaging with a tumor-associated antigen (shown in blue), while the other side of the molecule engages with a CD3 on a T cell (shown in green). Once bound, the T cell becomes activated and kills through the same mechanisms at the CAR cell lysis.

Mesothelin-targeting BiTEs were found to be highly effective at inducing complete remission in two PDX models of KMT2A rearranged AML. Because these studies were performed in immunodeficient mice, human T cells were injected to act as effector cells. BiTE molecules in the IgG format with a longer in vivo half-life were able to suppress the extramedullary tumor masses that are commonly observed in MV4;11 xenografted mice [ 63 ]. CAR-T cells targeting mesothelin were efficacious in controlling tumor burden by eradicating leukemia stem cells [ 61 ]. Most recently, work has been conducted using anti-mesothelin CAR NK-92 cells in AML samples. In vitro and in vivo studies revealed that these CAR NK-92 cells were effective at specifically targeting mesothelin+ AML samples while not killing mesothelin-negative samples [ 62 ]. These different modalities that target mesothelin provide effective targeted therapeutic options for mesothelin+ AML.

What is the role of mesothelin in AML? Of important clinical significance, in a review of patients with core binding factor AML, which traditionally confers a more favorable risk stratification, those with concurrent mesothelin expression had a statistically significant higher risk of relapse and worse disease-free survival [ 121 ]. Mesothelin expression was significantly associated with the presence of extramedullary disease, which may portend poor survival in AML patients [ 63 ]. Interestingly, mesothelin promoted leukemia growth and was also associated with extramedullary disease in AML xenograft models [ 122 ]. Mesothelin expression in leukemia stem cells suggests that similar to solid tumors, mesothelin may play a role in leukemia progression and relapse [ 61 ]. Further studies are necessary to shed light on the role of mesothelin in hematological malignancies.

In summary, recent findings of mesothelin overexpression in pediatric AML suggest this may be a useful target for therapy. Given the overall poor outcomes for children with AML, further studies to explore the use of mesothelin-directed immunotherapy are warranted. Pre-clinical studies utilizing anti-mesothelin CAR-T cells, BiTEs, and anetumab ravtansine against mesothelin-expressing AML exhibit tumor-specific killing of leukemia cells, and the ability to reduce leukemic burden in vivo. These studies of monotherapies as well as combination therapies with chemotherapy and/or immune checkpoint blockade inhibitors present a strong case for transition into clinical studies.

8. Conclusions

Mesothelin is a highly desirable target for tumor-specific immunotherapy given its overexpression in tumor cells and relative paucity in normal healthy cells. Currently, research seems to focus on the use of mesothelin to produce promising targeted therapy approaches, and to match the needs of the patient population and the tumor microenvironment specific to each cancer type. Many different targeted approaches allow for slight alterations that can improve and make the therapies more targeted in relation to difficulties, such as silencing immunosuppressive molecules. There still is a need, however, to identify the function of mesothelin, and other key characteristics of mesothelin, such as the unshed epitope to increase the therapeutic potential. While mesothelin has been considered a target for solid tumors, recent findings of mesothelin overexpression in AML point towards a further evaluation of the expression of this marker in other hematological malignancies. The absence of mesothelin on normal and healthy hematopoietic cells is of particular importance, as currently available immunotherapies for the treatment of AML are associated with hematopoietic toxicities.

Author Contributions

J.R.F. and D.H. wrote the manuscript. A.G., D.H., E.A.K., and S.P.B. conceptualized the work and edited the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Leukemia Research Foundation of Delaware, Lisa Dean Moseley Foundation, and the Nemours Foundation.

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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