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Amatuximab and novel agents targeting

mesothelin for solid tumors
This article was published in the following Dove Press journal:
OncoTargets and Therapy
8 November 2017
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Paolo Baldo Abstract: Mesothelin (MSLN) is considered a promising target for cancer therapy. Originally
Sara Cecco extracted in 1992 after the immunization of mice with a human ovarian cancer (OC) cell line
and cloned in 1996, MSLN seems to be involved in cell adhesion and metastasis. MSLN is
Pharmacy Unit, Directorate
Department, CRO Aviano-IRCCS prevalent in mesothelia tissues but is expressed in several human cancers, such as OC, pancre-
National Cancer Institute, Aviano, Italy atic cancer, mesothelioma, and lung cancer. Amatuximab (MORAb-009) is a mouse-human
chimeric monoclonal antibody with a selective affinity for MSLN. The principal mechanism of
action comprises inhibition of binding of MSLN with the antigen CA125/MUC16. The highest
phase of development is actually a Phase II trial (MORAb-009-201, Europe). In this review,
we describe the mechanism of action of amatuximab and other MSLN-targeting novel drugs,
along with a discussion about the expected efficacy, safety, and toxicity of this promising group
of agents and implications for future research and clinical practice.
Keywords: amatuximab, monoclonal antibody, mesothelin, antigen, mesothelioma, target
therapy

Plain language summary

Mesothelin (MSLN) is a glycoprotein, detectable on the surface of mesothelial cells. Although
its biological function in normal cells is completely clarified, it is overexpressed in many types
of cancer, and in cancerous cells, it may be involved in the promotion of cell proliferation, adhe-
sion and migration, chemotherapy resistance, and inhibition of apoptosis. MSLN seems to be an
interesting target in diagnosing and treating several solid tumors, in particular mesothelioma,
which, for the aggressive nature of the disease, still represents one of the concrete challenges
for modern oncology. In this review, we comprehensively describe MSLN as a potential target
for cancer therapy, along with a presentation of profiles of the new agents under investiga-
tion for mesothelioma and other solid tumors. A list of ongoing clinical trials is provided.

Introduction
Mesothelin (MSLN) is considered an interesting and promising target for cancer
research and therapy. It was initially identified as the cell surface antigen CAK1 by
Chang et al in 1992;1 then, it was characterized and cloned as a 40-kDa glycoprotein
detected on the surface of normal mesothelial cells.2 It is overexpressed by cancer cells
in mesothelioma, ovarian cancer (OC), pancreatic cancer (PC), and other solid tumors.
Correspondence: Paolo Baldo Relatively recent research detected high MSLN expression in acute myeloid leukemia3
Pharmacy Unit, Directorate Department, and in cholangiocarcinoma.4 The name “mesothelin” was assigned to highlight the
CRO Aviano-IRCCS National Cancer
Institute, Via F. Gallini, 2, Aviano
presence of the protein in normal mesothelial cells, including pleura, pericardium,
(PN) Italy fallopian tubes, trachea, and cornea.
Tel +39 0434 659221
Fax +39 0434 659743
The precursor, which is a 71-kDa protein that is encoded by a 2,138-bp-long cDNA
Email [email protected] and contains 628 amino acids, is then cleaved into two products, a ~31-kDa N-terminal

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http://dx.doi.org/10.2147/OTT.S145105
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region, called megakaryocyte potentiating factor (MPF), a combination of the two. MSLN is overexpressed in up to
and the ~40-kDa mesothelin protein, which is the main 95% of patients with the epithelioid form. In contrast, in the
form represented on the cell surface. MSLN is commonly a sarcomatoid form (10%–15% of all mesotheliomas), there
membrane-bound, glycosylphosphatidylinositol (GPI)-linked is no overexpression of MSLN.19,20
protein, but it is also detectable in a soluble form (soluble The crude annual incidence of MM in Europe is 2 new
MSLN protein [SMP]), which is shed from cancer cells.5 cases per 100,000, while the prevalence is 3.5 cases per
Patterns of MSLN expression in some types of cancer cells 100,000.21 According to data from the American Cancer
are characterized by using immunohistochemistry,6 exploit- Society, in the United States, the annual incidence is
ing the SAGE database,7 and using the antibody mAb5B2.8 estimated to be ~3,000 new cases per year.22,23 The global
Detection of MSLN in serum is a useful marker in cancer incidence trend indicates 36,925 incident cases in 2015
diagnostic procedures.9 versus 26,376 in 2005, with an overall change of 40% due
The biological function of MSLN in normal cells is to different factors (such as population growth, age trends,
not completely clarified. It is likely to be involved in cell and change in incidence).24
adhesion, differentiation, and signal transduction,10 and in The most important risk factor for the development of
cancerous cells, it may be involved in the promotion of MM is inhalation of asbestos, which induces oncogenesis via
proliferation, cell migration and spread, chemotherapy resis- the activation of the NF-κB-dependent pathway.25 Asbestos,
tance, and inhibition of apoptosis. The capability of MSLN whose principal components are two types of fibers, serpen-
to bind to the cancer antigen CA-125, also called mucin 16 tine and amphibole, was largely used until 1980s–1990s, for
(or MUC16), suggests that MSLN is involved in cell adhe- its excellent acoustic and thermal insulation properties and
sion and is an important target for innovative anticancer its mechanical strength. A very long latency period – up to
agent.11–13 The overexpression of MSLN activates multiple 25–40 years26 – can elapse before the development of this
intracellular pathways, including nuclear factor-kappaB tumor. Moreover, developed countries are gradually promot-
(NFκB), MAPK, and PI3K pathways, with the consequent ing laws to restrict the use of asbestos, which means that
promotion of cell proliferation, migration, and metastasis to some countries expect that the peak incidence has already
distal sites and the inhibition of apoptosis.14,15 Importantly, been reached. Other known risk factors include therapeutic
in recent years, the activation and stimulation of immune radiation27 and genetic factors.28
reactions using engineered T-cells with chimeric antigen Diagnostic procedures include imaging, cytology, and
receptors (CARs) allowed the characterization of antigens, immunohistochemistry, but, to date, no technique is consid-
including MSLN, overexpressed in solid tumors and in ered individually certain for the purposes of early diagnosis.29
several B-cell malignancies, including acute lymphoblastic Surgery is applied with a prognostic/palliative intent, while
leukemia, chronic lymphocytic leukemia, and non-Hodgkin standard chemotherapy is based on a treatment with cisplatin
lymphoma.16,17 combined with an antifolate (pemetrexed or raltitrexed). New
After the cleavage, MPF acts as a cytokine that stimulates therapeutic approaches under evaluation include angiogen-
colony formation in bone marrow megakaryocytes. MSLN esis inhibitors,30 mTOR inhibitors,31 and histone deacetylase
is a GPI-anchored cell-surface protein that performs cell inhibitors.32 Given the overexpression of MSLN in .80% of
adhesion modulating activities. total MM cases, new agents targeting MSLN under evalu-
ation in clinical trials are considered a very promising field
MSLN as a therapeutic target in for research and therapy.
mesothelioma
Mesothelioma is a rare cancer deriving from the mesothe- MSLN as a therapeutic target in
lium, which lines the pleura and other serous cavities (such other solid tumors
as the peritoneum, pericardium, and tunica vaginalis testis), MSLN seems to be overexpressed in ~30% of all cancers.33
is the main form of cancer in these structures, and is often MSLN expression in different types of solid tumors is
characterized by a poor prognosis. Mesothelioma is described described comprehensively by Hassan et al34 (see also The
in the benign or malign subtypes. Surgery is the choice option Human Protein Atlas).35
for the benign form, but in case of malign transformation, the
overall estimated survival is 24–36 months.18 The malignant Pancreatic cancer
form (malignant mesothelioma [MM]) has an epithelial PC was investigated for the expression of MSLN by Argani
morphology, or a fibrous one, also called sarcomatoid, or et al,36 Hassan et al,37 and Zervos et al,38 showing a high

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Dovepress Clinical targeting mesothelin for solid tumors

expression of MSLN for most of the pancreatic adenocarcino- adenocarcinoma, and its mature form was detected in 55%
mas but not in normal pancreatic cells. At the same time, their of patients.50
studies revealed the presence of MSLN in other adenocarci-
nomas of the biliary tract. Recent data confirm the hypothesis Head and neck cancers
that new immunotoxins actually investigated in clinical trials, The expression of MSLN in the human leptomeninges and
such as LMB-100 (previously named RG7787), might have meningiomas is not completely studied and understood.
synergistic anticancer effects when used in combination with There are similarities in the structure and functions of the
taxanes or other standard chemotherapy.39 pleura and leptomeninges, and this suggests that MSLN
might play a role in the meningeal function and could be
Ovarian cancer expressed in meningiomas.51 Future research is necessary
OC expresses, especially in the non-mucinous variant of to better understand the possible role of MSLN as a target
cancer cells, high levels of MSLN. Hanaoka et al40 showed for therapy of gliomas, meningiomas, and/or other head
that 68.8% of OCs and 24.2% of borderline-type tumors and neck cancers. The overexpression of MSLN was also
express high MSLN levels, with implications for a shorter determined by immunohistochemistry in thymic carcinomas,
progression-free survival (PFS) and overall survival (OS). An suggesting that MSLN is a potential important target for this
analysis of MSLN expression is currently being performed type of cancer.52,53
by using immunohistochemistry and imaging techniques
(immunoPET) with positron-emitting isotopes (89Zr-labeled Gastric cancer
mAbs and 64Cu-labeled mAbs) to evaluate the tumor uptake Tomoaki et al investigated the expression and extracellular
of innovative antibody-drug conjugate (ADC) immunothera- secretion of MSLN in human gastric cancer cell lines and
peutic agents.41,42 The resulting data will be helpful to predict found lower expression levels in the human gastric cancer
the potential utility and efficacy of new immunoconjugates compared to those noted in human mesothelioma cells,54
in the therapy of these types of cancer.43 and the levels were not specific to gastric cancer. Recently,
Han et al55 found that 25.6% of a cohort of 117 patients with
Breast cancer gastric carcinoma showed high levels of MSLN expression,
Currently, there is a plethora (451) of studies regarding which was associated with a poor prognosis. They concluded
targeted therapies for breast cancer (BC) (as reported in that MSLN-targeted therapies merit further research in
ClinicalTrials.gov trials register).44 However, only 5 studies patients with gastric carcinomas.
correlated with MSLN as the main biomarker (for refer-
ence see Table 1). In treating BC, MSLN, as a target, may MSLN targeting: amatuximab
be particularly promising for triple-negative breast cancers (MORAb-009)
(TNBC), one of the most aggressive forms of BC. Li et al Amatuximab (alternative names: MORAb-009, anti-MSLN
investigated MSLN as a prognostic BC biomarker, whose monoclonal antibody [MAb]) is a chimeric, humanized
expression is highly enriched especially in African–American IgG1/k MAb that targets the cell surface MSLN. The pre-
women.45 These results are consistent with data published by cursor of MORAb-009 was isolated by Chowdhury et al in
Bayoglu et al46 and Parinyanitikul et al,47 who, respectively, 199856 from a mouse splenic mRNA and was then optimized
reported a prevalence of 42.3% and 34% of patients express- by fusing the gene encoding MSLN Fv (SS1 scFv) with
ing MSLN in TNBC. However, they suggested that MSLN human IgG1 and kappa regions.57 Amatuximab consists
overexpression may not have a prognostic value and does in 83% of human and 17% of murine sequences, and it is
not correlate with the survival outcomes in patients with comprised of 2 identical heavy and 2 identical light chains
TNBC. Future work is needed to evaluate the potential of connected by disulfide bonds. The substance can poten-
MSLN-targeted therapy in the treatment of BC. tially reduce tumor growth by inhibiting MSLN binding to
the extracellular substrate and also by antibody-dependent
Lung cancer cellular cytotoxicity (ADCC). Amatuximab is not yet com-
Ordonez, Miettinen and Sarlomo-Rikala performed immu- mercially available, and the highest development phase is
nohistochemistry studies using the MSLN-specific antibody Phase II. It is actually investigated in trials for the treatment
5B2 and showed that 38%–40% of lung adenocarcinomas of pleural mesothelioma and PC in the USA, Europe, Canada,
stain positively for MSLN.48,49 In another study, the pres- and South America. Today, the primary focus is to evaluate
ence of the MSLN precursor was detected in 82% of lung its efficacy against mesotheliomas.

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Baldo and Cecco Dovepress

Pharmacology considered a balanced reference dose for efficacy and safety

Pharmacodynamics in ~80% of subjects. The serum concentration–time profile
After the characterization of amatuximab, Hassan et al57 of amatuximab suggests that after 5 weeks of weekly dos-
performed preclinical studies to investigate the ability of ing, 89% of the steady-state concentration level is reached.
amatuximab to target the MSLN protein expressed in some Factors, including weight, age, gender, and race, seem not
human cancer cells, to internalize in cancer cells after binding to influence the pharmacological effects of amatuximab.
MSLN and to exert ADCC. Combination schedules with other chemotherapy drugs, for
Results from the preclinical studies indicate a potential example, cisplatin and pemetrexed therapies, show syner-
relevant interaction between amatuximab and tumorigenic gic potentiation and reach a higher steady state Cmin. Other
cells/tissues overexpressing MSLN, and specifically: models to investigate the distribution of amatuximab in the
• In immunohistochemistry studies, MSLN-positive tumor body and the patterns of penetration in cancer formations are
cells show strong cell surface staining, as reported by based on imaging techniques using SPECT.65
investigational medicinal product (IMP) dossier and
by independent studies;1,58 Safety and expected toxicity
• In antibody-dependent cytotoxicity studies, amatuximab Amatuximab is actually under investigation in several
enhances ADCC in MSLN-positive cancer cell lines, international trials. For this reason, the safety profile is
but not at comparable levels in MSLN-negative cell implemented day after day following the adverse events
lines;59,60 (AEs) clinical reporting and applying pharmacovigilance
• In standard in vivo murine xenograft studies, Hassan signal detection. Phase I and Phase II studies investigated the
et al57 and Morphotek Inc. investigated the potential safety and tolerability of amatuximab; although indicating a
effects of amatuximab as a single agent or in combina- discrete tolerability, they showed that 54.2%62 to 76.5%64 of
tion with gemcitabine and rituximab. Amatuximab alone patients experienced AEs that were considered to be associ-
resulted in a significant reduction of tumor dimension in ated with the amatuximab treatment. Among a total of 41
the intervention group (amatuximab-treated) compared to patients in two studies (24+17, respectively), 10%–29.4%
the control group (29.9% difference). Rituximab had no experienced AEs (including cytokine release syndrome, hot
measurable effects, while some synergy with gemcitabine flushes, pyrexia, arthralgia, and nausea) that were potentially
was detected, as an additive effect; related to immune-mediated mechanism, which is relevant
• In adhesion blocking assays, amatuximab inhibited the to the fact that amatuximab is a MAb. Other common AEs
interaction of MSLN-expressing cells with MUC16- include fatigue (the most frequent), liver function elevation
expressing cells, a factor considered of great importance (AST, ALT, ALKP, and serum bilirubin), vomiting, decrease
for reducing cell adhesion, migration patterns, and finally in appetite and weight, headache, hypotension, dizziness, and
metastasis.61 allergic reactions. It is reported that only one patient died of
interstitial lung disease (ILD), and the cause was related to
Pharmacokinetics (PK) an AE to the amatuximab treatment.
Amatuximab, in actual clinical trials, is administered intra-
venously at the identified maximum tolerated dose (MTD) Genotoxicity/teratogenity/pregnancy: available data
of 200 mg/m2. The main available data about MORAb- To date, no genotoxicity or teratogenicity or pregnancy
009 PK are described by Hassan et al,62 Gupta et al,63 and studies have been planned and conducted for amatuximab.
Fujisaka et al.64 The population PK analysis of the data Amatuximab belongs to the pharmacological class of mono-
collected from previous Phase I and Phase II studies in clonal antibodies and is expected not to be genotoxic.
PC or malignant pleural mesothelioma (MPM) describes a
two-compartment model, incorporating parallel linear and Amatuximab in clinical studies
nonlinear (Michaelis–Menten) pathways for elimination Amatuximab is investigated in trials for the treatment of
from the central compartment. The nonlinear elimination is pleural mesothelioma and PC in USA, Europe, Canada, and
related to the interaction with the variable cell internalization South America. The primary intention of researchers is the
of the antigen-antibody complex Ab-MSLN. In summary, evaluation of its efficacy against mesotheliomas. An “inves-
PK studies estimate that a dose of 5 mg/kg, administered tigational new drug application” was launched by Morphotek
weekly, achieves a steady-state Cmin of 83.1 mg/mL and is for amatuximab in 2006.

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Dovepress Clinical targeting mesothelin for solid tumors

In this paper, we refer to amatuximab and other anti- amatuximab or a placebo. After four or six induction cycles,
MSLN agent studies citing the Clinical Trials Identifier (NCT the stable patients continued maintenance therapy with
number) in Medline (www.ClinicalTrials.gov).44 A summary either amatuximab or placebo. The PFS, ORR, objective
of the clinical trials of amatuximab for MSLN-expressing duration of response (DoR), and health-related quality of
tumors currently listed on ClinicalTrials.gov is presented life (QoL) were the principal secondary outcome measures.
in Table 2. In addition, the clinical development of the drug is ongoing.
Initially, a Phase I clinical trial (NCT00325494) was Two early Phase I mono-centric studies were conducted
planned,66 recruiting 24 subjects with PC or mesothelioma with the objective of investigating in vivo distribution
or non-small-cell lung cancer (NSLC) or OC. The primary and safety of 111In radio-labeled amatuximab in MSLN-
outcome measures included the evaluation of safety and expressing cancers (NCT0152132572 and NCT0141345173).
tolerability of amatuximab, the frequency and severity of Despite the small number of recruited patients (6 and 7,
the AEs and of the serious adverse events (SAEs), laboratory respectively), Lindenberg et al65 reported their findings
parameters, and cardiovascular examinations. The dose range that 111In-amatuximab showed a good tolerability, the
that was investigated was between 12.5 and 400 mg/m2. The dosimetry profile was favorable, and the physiologic uptake
MTD was set to 200 mg/m2. A similar Phase I clinical trial was detectable in the liver, kidneys, spleen, and heart.
(NCT01018784)67 was performed in 17 Japanese patients. The uptake of 111In-amatuximab was higher in mesothe-
The aims of the study were to determine dose-limiting tox- liomas compared to PCs. This study was realized with the
icity (DLT) and MTD. In this trial, Fujisaka et al64 reached objective of refining imaging techniques in patients with
similar conclusions, and the weekly dose was determined advanced cancers.65
to be 200 mg/m2. Taking into account an acceptable safety
profile and the potential of obtaining clinical benefit, a MSLN targeting: novel agents
subsequent Phase II, multicentric, single-arm, open-label MSLN expression is rather limited in normal tissues, but it is
trial (NCT00738582)68 recruited 89 patients presenting highly elevated in some solid human tumors, such as malig-
unresectable MPM, naïve to chemotherapy. Amatuximab nant mesothelioma, PC, OC, and lung adenocarcinoma. This
was administered in association with standard chemotherapy provides the rational basis to test different agents potentially
regimens, with the primary objective to improve PFS. The targeting MSLN.
secondary outcome measures were the OS, overall response A summary of new agents undergoing clinical evaluation
(OR), and evaluation of the safety profile of amatuximab. The is presented in Table 1, including monoclonal antibodies, in
PFS was not improved in the treatment group compared to the form of single agents or as ADCs, immunotoxins, vac-
the controls. However, the combined therapy of amatuximab cines, and chimeric T-cells, containing Fv fragments that
plus pemetrexed/cisplatin gave encouraging results in terms recognize MSLN.
of the median OS (14.8 months) and the objective response
rate (ORR) (39%).69 SS1P
The study NCT0057071370 was a Phase II, double-blind, SS1P is a recombinant anti-MSLN immunogenic toxin
randomized controlled trial, in which amatuximab was that is constructed by the fusion of a variable fragment of a
administered with gemcitabine in patients with unresectable murine anti-MSLN antibody with the pseudomonas exotoxin
PC. The patients were randomized to gemcitabine alone or 38 (PE38) portion. SS1P was tested both as a single agent
gemcitabine plus amatuximab. The primary outcome was and in combination with chemotherapy.57,69,74 In one early
OS, and the secondary outcome measures were PFS and best Phase II clinical trial (NCT01362790),75 SS1P was adminis-
ORR. The treatment arm (gemcitabine plus placebo) showed tered in combination with pentostatin and cyclophosphamide
better results compared to amatuximab, for all the three main with the aim of decreasing the immunogenicity of SS1P in
outcomes, but no statistical analysis was provided. The posted patients with mesothelioma, lung cancer, or PC. The primary
data are available at www.ClinicalTrials.gov.44 objectives of this study were to evaluate the tolerability and
NCT0235714771 (acronym: ARTEMIS) was another safety of a regimen of pentostatin and cyclophosphamide in
Phase II clinical trial, started in 2015 with the main objec- combination with SS1 (dsFv)PE38 and to evaluate the ORR
tive to evaluate the OS in patients with previously untreated, stratified by tumor type and the formation of antibodies SS1P.
unresectable MPM. The standard chemotherapy regimen The rationale was that the administration of a conditioning
was administered to all the patients in combination with regimen of pentostatin plus cyclophosphamide delays the

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 Table 1 Summary of clinical trials investigating new agents targeting mesothelin expressing tumors

5342
Study ID Phase Start date/ Sponsor or principal Agent or Condition Intervention Main outcome measures
(ClinTrial.gov) recruitment status investigating research pharmacological
institute mechanism
Baldo and Cecco

NCT01445392* I November 13, 2007/ NCI; CC SS1P Mesothelioma Multicycle or single Safety and MTD

Dovepress
completed cycle SS1P Best ORR
Pemetrexed
Cisplatin
NCT01362790* I May 11, 2011/active, NCI; CC SS1P Mesothelionma SS1(dsFv)PE38 ORR
II not recruiting Lung adenocarcinoma Pentostatin SSP1 antibody formation
Pancreatic neoplasms Cyclophosphamide Grade of ADEs
OS; PFS; DoR

submit your manuscript | www.dovepress.com

NCT01051934* I December 29, 2009/ NCI; CC SS1P NSCLC SS1(dsFv)PE38 Safe and tolerable doses
completed Adenocarcinoma Paclitaxel Pharmacokinetics
Carboplatin DoR; ORR
Bevacizumab
NCT00066651* I July 2003/completed NCI; (NCI) SS1P Mesothelioma SS1(dsFv)PE38 NA
Solid tumors immunotoxin
NCT00006981* I December 2000/ NCI; (NCI) SS1P Mesothelioma SS1(dsFv)PE38 NA
completed Solid tumors immunotoxin
NCT02810418* I June 10, 2016/ NCI; CC LBM-100 Neoplasms LBM-100 ORR, MTD, safety and tolerability of
II recruiting Pancreatic neoplasms Nab-paclitaxel LBM-100+ Nab-paclitaxel
NCT02798536* I June 7, 2016/ NCI; CC LBM-100 Mesothelioma LBM-100 MTD; average time from treatment
recruiting Nab-paclitaxel initiation to disease progression
or death; proportion of patients
at MTD at RECIST; listing and
frequency of treatment-related ADEs
NCT03006302* II June 2017/not yet Sidney Kimmel CRS-207 Metastatic pancreatic CRS-207 6 months survival; recommended
recruiting Comprehensive Cancer adenocarcinoma Epacadostat dose of Epacadostat; 6 months
Center Pembrolizumab survival; OS; PFS; ORR; immune-
GVAX related duration of response
NCT02575807* I January 2016/ Aduro Biotech Inc.; Incyte CRS-207 Platinum resistant: CRS-207 Number of patients reporting
II recruiting Corporation Ovarian cancer Epacadostat hematologic and non-hematologic
Fallopian cancer Pembrolizumab DLTs; Adverse events by CTCAE
Peritoneal cancer grades; ORR; PFS
NCT02243371* II December 2014/ Sidney Kimmel CRS-207 CRS-207 OS; number of patients experiencing
active, not recruiting Comprehensive Cancer Nivolumab treatment-related ADEs; TTP; tumor
Center; Bristol MS; CY marker kinetics
Aduro Botech; American
Association for Cancer
Research

OncoTargets and Therapy 2017:10

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 NCT02004262* II January 2014/ Aduro Biotech Inc. CRS-207 2nd line, 3rd line and CRS-207 OS; treatment-related ADEs
completed greater metastatic GVAX
pancreatic cancer Gemcitabine
Dovepress

Capecitabine
Erlotinib
Irinotecan
Cyclophosphamide
NCT03102320* I May 26, 2017/ Bayer Anetumab-R Neoplasms Anetumab-R MTD; ORR; ADEs; DoR; DRR; PFS
recruiting Gemcitabine
Cisplatin

OncoTargets and Therapy 2017:10

NCT03023722* II May 11, 2017/ Howard Hochster; Bayer; Anetumab-R Pancreatic cancer Anetumab-R Response rate as measured per
recruiting Yale University RECIST criteria; TTP; toxicity
NCT02839681* II June 2017/recruiting NCI; CC Anetumab-R Lung neoplasms Anetumab-R Recommended Phase II dose; ORR;
PFS; DoR; OS
NCT02824042* I September 7, 2016/ Bayer Anetumab-R Medical oncology Anetumab-R QRS Interval duration; QT interval
recruiting Itraconazole duration; cycle 1+2 AUC; incidence
of serious and non-serious ADEs
NCT02751918* I June 8, 2016/ Bayer Anetumab-R Ovarian neoplasms Anetumab-R MTD; incidence of serious and
recruiting PEGylated non-serious ADEs; AUC; incidence
liposomal of positive anti-drug antibody
doxorubicin interaction; incidence of positive
neutralizing antibody iter
NCT02696642* I August 14, 2016/ Bayer Anetumab-R Neoplasms Anetumab-R Incidence of treatment-related ADEs,
recruiting cycle 1 AUC; pharmacokinetics;
immunogenicity as defined by the
titer of anti-anetumab-R antibodies;
immunogenicity as defined by
incidence of neutralizing antibodies
NCT02639091* I February 3, 2016/ Bayer Anetumab-R Medical oncology Anetumab-R MTD; plasma concentration of
recruiting Pemetrexed anetumab-R; tumor response
Cisplatin evaluation following mRECIST
criteria; number of patients with a
positive titer of anti-drug antibodies
NCT02610140* II December 3, 2015/ Bayer; ImmunoGen and Anetumab-R Mesothelioma Anetumab-R OS; PFS; ORR; DoR; number of
active, not recruiting MorphoSys Vinorelbine patients with serious ADEs as a
measure of safety and tolerability
NCT02485119* I August 14, 2015 Bayer Anetumab-R Neoplasms Anetumab-R Number of treatment-related AEs as
Breast cancer a measure of safety and tolerability;
pharmacokinetic parameters for
Bay 94-9343 (Cmax, AUC, tmax);

Dovepress
submit your manuscript | www.dovepress.com
tumor response based on RECIST;
level of MSLN expression using
immunohistochemistry
(Continued)

5343
Clinical targeting mesothelin for solid tumors
 Table 1 (Continued)

5344
Study ID Phase Start date/ Sponsor or principal Agent or Condition Intervention Main outcome measures
(ClinTrial.gov) recruitment status investigating research pharmacological
institute mechanism
Baldo and Cecco

NCT01469793* I November 2011/ Genentech, Inc. DMOT4039A Metastatic pancreatic DMOT4039A MTD; Number of patients with

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completed adenocarcinoma DLTs; recommended Phase II dose
Platinum-resistant ovarian
cancer
NCT02341625* I January 2015/active, Bristol-Myers Squibb BMS-986148 Mesothelioma BMS-986148 Number and grade of AEs
not recruiting NSCLC Nivolumab
Ovarian cancer
Pancreatic cancer

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Gastric cancer
NCT02884726* I–II August 2016/active, Bristol-Myers Squibb BMS-986148 Advanced and/or BMS-986148 Incidence and grade of AEs and
not recruiting metastatic solid tumors SAEs;
NCT02792114* I June 2016/recruiting Memorial Sloan Kettering Mesothelin- Breast cancer Cyclophosphamide, MTDs
Cancer Center targeted T-cells Metastatic HER2-negative mesothelin-targeted
breast cancer T-cells
NCT02930993* I August 2016/ China Meitan General CAR-T-cells Mesothelin-positive Antimesothelin Safety of infusion of autologous anti-
recruiting Hospital tumors CAR-T-cells mesothelin CAR-T-cells; treatment
Marino Biotechnology Ltd. response rate of anti-mesothelin
CAR-T-cells; PFS;
OS; proliferation of antimesothelin
CAR-T-cells in patients; activation of
anti-mesothelin
CAR-T-cells in patients; •persistence
of antimesothelin
CAR-T-cells in patients
NCT03030001* I–II February 15, 2017/ Ningbo Cancer Hospital CAR-T-cells Solid tumor PD-1 antibody Safety of infusion of autologous
recruiting Adult advanced cancer expressing mesothelin-specific CAR-T-cells;
mesothelin-specific response evaluation criteria of solid
CAR-T-cells tumor; PFS; OS
NCT02706782* I March 2016/ Shanghai GeneChem CAR-T-cells Pancreatic cancer TAI-meso Number of patients with ADEs;
recruiting Co., Ltd. CAR-T-cells number of patients with tumor
response; detection of transferred
T-cells in the circulation using
quantitative methods (PCR)
NCT01583686* I March 30, 2012/ NCI; CC CAR-T-cells Cervical cancer Anti-mesothelin Determine a safe dose and
recruiting Pancreatic cancer CAR determine if this approach will result
Ovarian cancer Fludarabine in an objective tumor regression;
Mesothelioma Cyclophosphamide determine the in vivo survival of
Lung cancer Aldesleukin CAR gene-engineered cells

OncoTargets and Therapy 2017:10

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 NCT02580747* I October 2015/ Chinese PLA General CAR-T-cells Malignant mesoteliomas Anti-meso-CAR Occurrence of study-related adverse
recruiting Hospital Pancreatic cancer vector transduced events; anti-tumor responses to
Ovarian tumor T-cells CAR-T-meso cells infusions
Dovepress

Triple-negative breast
cancer
Other mesothelin-
positive tumors
NCT01355965* I May 2011/active, not University of Pennsylvania CAR-T-cells Malignant pleural Autologous T-cells AEs; ORR
recruiting mesothelioma
NCT02414269* I May 2015/recruiting Memorial Sloan Kettering CAR-T-cells Malignant pleural disease iCasp9M28z T-cell Composite measure of severity and

OncoTargets and Therapy 2017:10

Cancer Center Mesotheliomas infusions number of AEs; changes in serum
Metastases Cyclophosphamide levels of the biomarker soluble
Lung cancer mesothelin-related peptide
Breast cancer
NCT03054298* I March 1, 2017/ University of Pennsylvania CAR-T-cells Lung adenocarcinoma Hu-CAR-T-meso Number of participants with
recruiting Ovarian cancer cells treatment-related ADEs; clinical
Peritoneal carcinoma anti-tumor effect by RECIST criteria
Fallopian tube cancer (modified for mesothelioma); PFS;
Mesotheliomas OS
NCT02159716* I June 2014/completed University of Pennsylvania CAR-T-cells Metastatic pancreatic CAR-T-meso Number of ADEs
adenocarcinoma
Epithelial ovarian cancer
Malignant epithelial
pleural mesothelioma
Note: *All trial information is available at https://ClinicalTrials.gov/ct2/show/[NCTidentifier].
Abbreviations: ADEs, adverse drug events; AEs, adverse events; AUC, area under the curve; CAR, chimeric antigen receptor; CC, National Institutes of Health Clinical Center; CTCAE, common terminology criteria for adverse events;
CY, cyclophosphamide; DLT, dose-limiting toxicity; DoR, duration of response; DRR, durable response rate; MSLN, mesothelin.; MTD, maximum tolerated dose; NA, not available; NCI, National Cancer Institute; NSLC, non-small-cell
lung cancer; ORR, objective response rate; OS, overall survival; PCR, polymerase chain reaction; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors; SAEs, serious adverse drug events; TTP, time to
progression.

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Clinical targeting mesothelin for solid tumors
 Table 2 Summary of clinical trials investigating MORb-009 for mesothelin expressing tumors

5346
Study ID-NLM Phase/number Start date/ Sponsor or principal Agent or Condition Main outcome measures Posted/published data
identifier of patients recruitment investigating pharmacological (OS/PFS/other)
(other acronyms) enrolled status research institute mechanism
Baldo and Cecco

NCT0032549455,60 Phase I/24 May 2006/ Morpohtek MORAb-009 Pancreatic cancer Safety and tolerability as a measure NA

Dovepress
(MORAb-009-001) completed Mesothelioma of ADE; safety and tolerability as
Ovarian cancer a measure of clinical laboratory
NSCLC parameters; pharmacokinetics of
MORAb-009; OTR; percentage
of patients with antibodies against
infliximab

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NCT0101878457,61 Phase I/17 November 2009/ Eisai CO. Ltd; Eisai Inc. MORAb-009 Cancer DLT; complete response and partial NA
(MORAb-009-J081-102) completed mesothelin- response; best overall response
positive rate in the RECIST evaluation
NCT0073858262,63 Phase II/89 December 2008/ Morphotek MORAb-009 Malignant pleural OS; PFS; best overall response rate PFS (months): 6.1 (in 51%
(Amatuximab/MORAb- completed Pemetrexed mesothelioma treated pts) (95% CI: 5.8, 6.4)
009-003) Cisplatin OS (months): 14.8 (95% CI:
12.4, 18.5)
NCT0057071364 Phase II/155 December 2007/ Morphotek MORAb-009 Pancreatic cancer OS; PFS; best overall response rate PFS (months): 3.4 (95% CI: 1.9,
(MORAb-009-002) completed Placebo 4.7) vs 3.5 (95% CI: 2.8, 4.9)
Gemcitabine OS (months): 6.5 (95% CI: 4.5,
8.1) vs 6.9 (95% CI: 5.4, 8.8)
NCT0235714765 Phase II/108 November 2015/ Morphotek Placebo Mesothelioma, OS; PFS; ORR; DoR; health-related NA
(ARTEMIS) active, not MORAb-009 malignant QOL; evaluate ADEs and AEs
recruiting Pemetrexed
Cisplatin
NCT0152132558,66 Phase I/6 September 2011/ Morphotek MORAB-009 Pancreatic cancer Determine biodistribution of NA
(MORAb-009-201) completed Mesothelioma radiolabeled amatuximab in tumor
Ovarian cancer and non-tumor tissue; safety of
NSCLC a single IV of indium-CHX-A
amatuximab; pharmacokinetics and
serum level; uptake of indium-
CHX-A amatuximab; correlate
shed serum mesothelin to imaging
NCT0141345167 Phase I/7 July 2011/ National Cancer MORAb-009 Carcinoma, Biodistribution of radiolabeled NA
terminated Institute; National pancreatic ductal amatuximab in tumor and non-
Institute of Health Mesothelioma tumor tissue; background ratio and
Cancer Center Ovarian maximum counts; CTCAE ADEs;
neoplasms pharmacokinetics; antibody uptake
NSCLC versus IHC mesothelin expression
Abbreviations: ADEs, adverse drug events; AEs, adverse events; CHX-A, (isothiocyanatobenzyl)-cyclohexyl-; CI, confidence interval; CTCAE, common terminology criteria for adverse events; DLT, dose-limiting toxicity; DoR, duration
of response; IHC, immunohistochemistry; IV, intravenous; MORb-009, amatuximab); NA, not available or not appropriate; NSCLC, non-small-cell lung cancer; ORR, objective response rate; OS, overall survival; OTR, objective tumor
response; PFS, progression-free survival; QOL, quality of life; RECIST, Response Evaluation Criteria in Solid Tumors.

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formation of anti-SS1P antibodies, allowing patients to MPM (NCT01675765).86 The main outcome measures are
receive multiple cycles of SS1P and, thus, potentiating the safety, the number of subjects reporting AEs, the induction
expected efficacy. of an immune response to MSLN by enzyme-linked immu-
No data are actually available about a (completed) Phase I nosorbent spot assay, the objective tumor response and the
trial (NCT01051934)76 in which SS1P is administered in time to progression. To date, no data have been posted about
association with paclitaxel, carboplatin, and bevacizumab the results of this trial.
in lung adenocarcinoma.
BAY 94-9343
LMB-100 BAY 94-9343, also called anetumab ravtansine is an anti-
LMB-100 (previously named RG7787) is a recombinant body drug, conjugate to DM4, which is a tubulin polymerase
immunogenic toxin targeting MSLN. It is based on a inhibitor. Anetumab is designed to target MSLN on the
humanized Fab fragment with a newly engineered PE24 cell surface and release the maytansinoid tubulin inhibitor
and is conceived to reduce the induction of immunogenicity into the cytoplasm after antibody internalization.87 In vitro,
compared to SS1P. Two initial Phase I–II studies, started anetumab is markedly and selectively cytotoxic for MSLN
in June 2016, are recruiting patients with malignant meso- overexpressing cells.
thelioma (NCT02798536)77 and pretreated patients with Several Phase I studies are still recruiting patients
pancreatic adenocarcinoma (NCT02810418).78 Recent data presenting different malignancies. An early Phase II study
published by Zhang et al79 showed that LMB-100 enhanced (NCT02610140),88 started in December 2015, investigated
its activity when it was used in combination with the taxane anetumab at a dose of 6.5 mg/kg, administered as a mono-
Nab-paclitaxel in treating mesothelioma. therapy to patients with pretreated MPM compared to
vinorelbine as standard therapy. The primary objective is
CRS-207 to test the superiority of anetumab ravtansine in PFS. The
CRS-207 is a live attenuated, recombinant Listeria mono- secondary outcome measures include the OS, DoR, ORR,
cytogenes designed to express MSLN and secrete it in the patient-reported outcomes, and number of patients reporting
cytosol of the infected antigen-presenting cells.80 ADEs as a measure of safety and tolerability. The study is
It shows a synergic activity in combination with GVAX active but is not actually recruiting patients.
pancreas, a cell vaccine expressing human granulocyte Anetumab has reached Phase II of clinical development
macrophage-colony-stimulating factor and a regimen of as a single agent in PC (NCT03023722)89 and lung cancer
low dose cyclophosphamide, administered to potenti- (NCT02839681),90 and these two studies just started to recruit
ate antineoplastic activity and inhibit regulatory T-cells. patients (May and June 2017, respectively). Another trial is
In a Phase II clinical trial, cyclophosphamide/GVAX and investigating anetumab in combination with pembrolizumab
CRS-207 prolonged survival in patients with PC with a for MPM (NCT03126630).91
favorable toxicity.81 The same combination was investigated
in pretreated patients with metastatic adenocarcinoma of DMOT4039A
the pancreas compared to chemotherapy standard regimens DMOT4039A is an ADC consisting of the humanized IgG1
or to CRS-207 as a single agent (NCT02004262).82 Two anti-MSLN mAb h7D9.v3 (αMSLN), combined with the
other Phase II studies are active. Although they are not yet antimitotic agent monomethyl auristatin E, by means of a
recruiting patients, they intend to combine GVAX/CRS- protease-labile linker. After binding the ADC to the spe-
207 with nivolumab (NCT02243371)83 or CRS-207 with cific biological antigen, the complex MSLN-ADC is then
epacodostat, an inhibitor of indolamine 2,3-dioxygenase internalized, and the free form is released into the cytosol,
(NCT03006302),84 and this study started in June 2017, which induces G2/M-phase growth arrest, cell death, and
with the aim of improving survival in the same setting. apoptosis.92 The specific antiproliferative activity in vitro
CRS-207 and epacadostat are also under investigation in and its potent antitumor activity in xenograft cancer models93
OC (platinum-resistant), peritoneal tumor, and fallopian encourage researchers to test DMOT4039A in clinical
tumor (NCT02575807).85 trials. A multicenter, open-label, Phase I study is planned
The combination of CRS-207 with cyclophosphamide to assess the safety, tolerability, and PK of DMOT4039A
and standard chemotherapy was tested in a Phase I study that in patients with unresectable PC or platinum-resistant OC
was completed in June 2017, which enrolled 60 patients with (NCT01469793).94 Cohorts of participants receive escalation

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doses of DMOT4039A. A total of 54 out of the 71 enrolled recognizing the target antigen via the scFv-binding domain,
patients were treated every 21 days, and MTD was assessed this results in T-cell activation in a major histocompatibility-
at 2.4 mg/kg. Alternatively, in a weekly regimen, the dose independent manner.101 The possibility to adapt the binding
was determined to be 1 mg/kg. Across both the schedules, moiety, while retaining the principal structure, confers CARs
the most common toxicities were gastrointestinal symptoms. the opportunity to recognize any type of target and, therefore,
In addition, grade 3 hyperglycemia and grade 3 hypophos- to potentially affect any type of specific-antigen-expressing
phatemia, at 2.8 mg/kg, caused an interruption of dose cancer. CARs demonstrate promising results against hema-
escalation. A total of 6 patients (4 OC; 2 PC) had confirmed tologic malignancies and show only minor results in the
partial responses with DMOT4039A at 2.4–2.8 mg/kg every treatment of solid tumors. Few data on clinical trials are
21 days.95 published to date. A summary of the ongoing trials involving
CARs for solid tumors overexpressing MSLN was recently
BMS-986148 reported by Wang et al.102
BMS-986148 is an anti-MSLN MAb-cytotoxic drug conju- A major concern with CARs is the potential dramatic
gate. No data are available about the detailed pharmacology risk of toxicity, predominantly labeled “on-target/off-tumor”
of this agent, but it might be related to ADC MDX-1204, toxicity and as a “cytokine stench phenomenon”;103 and prob-
a MAb conjugated with the potent alkylating agent duocar- ably, this is one of the reasons why clinical trials investigating
mycin (MED2460).96 After cellular internalization, this agent CARs are proceeding at moderate speed.
prevents proliferation, leading to cell death and apoptosis. An
initial first Phase I study planned to investigate the safety and Discussion and future perspectives
tolerability of BMS-986148 in combination with nivolumab, The only realistic weapon currently available in modern
with the principal aim of highlighting the most hazardous oncology is the identification of new biological targets and
AEs and SAEs (NCT02341625).97 The secondary outcome biomarkers, essentially specific to the single type of cancer,
measures consisted of the evaluation of PK parameters, and an increasingly detailed understanding of their biologi-
immunogenicity, and a better understanding of pharmaco- cal pathways.
dynamics. The anti-tumor activity was defined in terms of Although, in recent decades, it has been possible to
the ORR, DoR, PFS, and OS. This Phase I–II study should increase the OS or PFS in many patients, some types of
enroll a total of more than 400 patients with MM, NSCLC, cancer remain a concrete challenge for modern oncology.
OC, PC, and gastric cancer. A smaller parallel Phase I study Important factors such as the difficulty of obtaining a pre-
(NCT02884726)98 started in October 2016 in a single center cise diagnosis when the disease is still at an early stage, the
in Japan, with preliminary data planned by the end of 2017, aggressive nature of the disease, or a poor differentiation in
is expected to provide important information about safety the expression of biomarkers between healthy and malig-
and tolerability of BMS-986148 in subjects with advanced nant cells are critical key points that still make it difficult to
and/or metastatic solid tumors. manage some cancers. Mesothelioma certainly falls into this
“difficult” cancer group and still requires more knowledge
CARs specifically aimed at understanding how the inflammatory
CARs are cited by the journal Science as one of the processes, as in the case of asbestos, which has a very long
“breakthroughs of 2013,”99 representing a promising concept latency period, are triggered.
of bio-immunotherapy. CARs are obtained by the combina- Although the global use of asbestos, considered as – albeit
tion of an antigen-recognition domain on the cell surface, not unique – the main cause of mesothelioma, is banned
derived from the single-chain variable fragment (scFv) and in most advanced countries since the 1980s and 1990s,
one (in first-generation CARs) or more (in third- to fourth- the long latency prior to diagnosis of mesothelioma (up to
generation CARs) stimulatory domains inside the cell, which 40 years)26,104 suggests that the incidence peak has not yet
activate an immunologic response.100 The concept that led to been reached in many countries. Furthermore, a very poor
CARs, together with adoptive T-cell processes, represents one prognosis after diagnosis of mesothelioma (12–24 months)
of the main strategies applied to manipulate patient T-cells makes it really urgent to implement research on how to treat
ex vivo, a process which involves removing the patient’s mesotheliomas. Treatment options depend on the age and
T-cells, genetically modifying them and infusing them back status of the patients and on the stage at diagnosis. Surgery
into the patient. However, because the CARs are capable of is not considered sufficient without adjuvant therapy, and

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Dovepress Clinical targeting mesothelin for solid tumors

thus, several chemotherapy programs are applied, includ- treatment, including a combination of an immune suppression
ing cisplatin, the antimetabolites pemetrexed or raltitrexed, therapy with pentostatin and cyclophosphamide, which
gemcitabine, vinorelbine and, optionally, a combination with demonstrated its clinical value. Several other strategies
antiangiogenic agents like bevacizumab.18,105 for reducing the immune response are under investigation,
MSLN, along with other biomarkers, is one of the targets and they are included in actual research programs. Zhang
that researchers are currently focusing on for diagnosing et al79 recently showed that LMB-100, in combination with
and treating mesotheliomas. Although the role of MSLN the taxane Nab-paclitaxel, in treating mesothelioma, has
in cancer progression is not yet completely understood,106 a synergistic activity, which could be useful in mitigating
many drugs targeting MSLN are currently under investi- immunogenicity.
gation in international, multicentric clinical trials. Hassan Antibodies against MSLN have a more efficient anti-tumor
et al,34 Zhao et al,96 and, recently, Mancuso and Neal107 activity when they are conjugated with a cytotoxic molecule
comprehensively reviewed the main strategies for targeting compared to the unconjugated drug, as demonstrated in pre-
MSLN in mesothelioma and other solid tumors. By reading, clinical and clinical studies.96 DM4, conjugated with anetumab,
in parallel, the data summarized by Hassan’s review34 and performs its cytotoxic activity mainly against rapidly replicat-
the results of Inaguma’s original immunohistochemistry ing cells, reducing systemic toxicity, and, thus, widening its
research53 (using anti-MSLN antibodies 5B2 and MN-1), it therapeutic window. Like other ADCs, it shows a favorable
is easy to appreciate how MSLN overexpression in many PK profile in terms of its half-life, increasing its therapeutic
solid tumors makes this target a formidable potential ground exposure with a less frequent dosing and limiting immuno-
for oncology research. genicity. On the other hand, the main toxicity associated with
In the present paper, we describe the pharmacological maytansinoid is the reduction of neutrophilis, lymphocytes,
profile of the promising anti-MSLN agent amatuximab, reticulocytes, and platelets along with hepatotoxicity.110,111
along with a summary of respective clinical trials (Table 2). In conclusion, MSLN is shown to be a promising target for
Furthermore, we propose emerging data about prognostic the treatment of several types of cancer. In treating BC, for
factors in some solid tumors and updates about new agents example, MSLN may be particularly promising for the TNBC
targeting MSLN that are currently being investigated and form, in which it is reported that up to 42.3% of patients show
provide an updated summary of the ongoing clinical trials (on overexpression of MSLN.47 In lung adenocarcinoma, MSLN,
Table 1), including those started in 2016 and 2017 (Table 1). in its mature form, is detected in 55% of patients,50 and in
Amatuximab, an unconjugated antibody against MSLN, gastric carcinomas, the detection of elevated levels of MSLN
has an acceptable safety profile, but when it is used as a single is correlated with a poor prognosis.55
agent, it shows only modest results in terms of stabilizing Different therapeutic strategies are under investigation
the disease.57,64 Nevertheless, a combination of amatuximab after obtaining promising preclinical results. The real goal
with chemotherapy shows clinical activity with no overlap- will now be to enhance its efficacy, to identify patients
ping toxicities, in Phase II trials. These findings encourage who can achieve the best benefit, and to limit drug-related
researchers to perform additional studies with different toxicities.
chemotherapy combinations. Recent Phase I and II clinical trials reinforced the
Immunotoxins are also considered a promising therapeu- hypothesis that MSLN is an important target for immuno-
tic strategy. However, to date, the main problem in using therapy, and the objective is to confirm these preliminary
anti-MSLN recombinant immunotoxins is immunogenic- data. At the same time, other studies should be designed
ity. A Phase I study shows that almost all of the enrolled to validate the utility of MSLN as a surrogate biomarker,
patients develop anti-toxin antibodies after treatment with thus making MSLN a predictor of the potential response
SS1P in combination with pemetrexed and cisplatin.69 to therapy. Serum MSLN laboratory assessment is a useful
Among the cohorts of patients treated with PE38-RIT, strategy for the future development of MSLN-targeted thera-
only one anaphylactic reaction was detected, after the first pies, helping to select and recruit patients who can achieve
infusion of immunotoxin.108 Although immune-mediated the best expected benefits by this type of treatment. To date,
reactions are very frequent, usually they are not serious. soluble MSLN is the only tumor biomarker that has been
Skin rashes, even severity grade 3, are effectively treated approved by the US Food and Drug Administration for treat-
with steroids.109 Many efforts have been made to reduce the ing mesotheliomas.112 For the purpose of selecting patients
immunological response to increase the effectiveness of the with the highest chance of benefit from the treatment, another

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research arm is focusing on PET and SPECT evaluation 8. Ordóñez NG. Application of mesothelin immunostaining in tumor
diagnosis. Am J Surg Pathol. 2003;27(11):1418–1428.
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The authors report no conflict of interest in this work. cancer/malignant-mesothelioma/about/key-statistics.html. Accessed
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