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tumor 1 (WT1) also represent promising targets for CAR-T cell therapies in MPM. FAP is highly expressed
[49]
in the tumor microenvironment, particularly in cancer-associated stromal cells . In a phase I trial, the anti-
FAP CD8+ CAR-T cell intrapleural administration tested on three patients was safe (NCT01722149). No
serious adverse events were reported [50,51] . WT1 is a protein expressed in both epithelioid and non-
epithelioid MPM. An ongoing phase I/II trial using anti-WT1 TCR T cells in MM patients expressing WT1
and human leukocyte antigen (HLA)-A*0201 is ongoing. To increase their efficacy, central memory and
naïve CD8+ T cells have been selected for TCR transduction (NCT02408016). Other promising targets
[54]
[53]
[52]
tested in preclinical studies include MET , Pan-ErbB T4 , 5 T4 , chondroitin sulfate proteoglycan 4
(CSPG4), and angiogenesis [55,56] . Therapeutic cancer vaccines represent another attractive therapeutic
approach that aims to stimulate an antitumor immune response with the administration of engineered
[57]
dendritic cells (DCs), genetic material, or peptides . A long-lasting experience in DC vaccine has permitted
the development of this approach in MPM. Based on promising preclinical results generated in mouse
models , a phase I study with DC vaccine in MPM patients was conducted (NCT00280982). In the study,
[58]
three patients (30%) obtained a partial response, and overall, the treatment showed a good safety profile .
[59]
In another phase I clinical trial, the autologous DC vaccine was combined with low-dose cyclophosphamide
in 10 pretreated MPM patients (NCT01241682). The combination regimen showed a good safety profile and
an antitumor effect in 7/10 patients, obtaining a survival of ≥ 2 years. After 50 and 66 months, 2 of 10
patients were alive . Due to these impressive, although preliminary results, a phase II/III trial
[60]
(NCT03610360) is ongoing. This trial is evaluating DCs loaded with allogeneic tumor cell lysates as
maintenance therapy after first-line chemotherapy (DENIM trial), having OS as the primary endpoint .
[61]
An additional attractive study is the phase Ib MESOVAX (NCT03546426), i.e., investigating the efficacy of
an autologous DC vaccine in combination with pembrolizumab in pretreated MPM or peritoneal
mesothelioma patients. The study is currently recruiting.

Genetic vaccines, including DNA, RNA, and viral-based vaccines, aim to improve the antigen-specific
antitumor immune response [62-67] .

Several types of oncolytic viruses have been tested in various preclinical and clinical trials for the treatment
of MPM [66,67] . Currently, a phase I clinical study is investigating the efficacy and safety of the intrapleural
administration of an oncolytic measles virus (MV-NIS virus) in 15 MPM patients (NCT01503177).

WT1 is also considered as a potential target, not only for the development of CAR therapy but also for
peptide vaccines in MPM patients . In a randomized, phase II clinical trial (NCT01265433), pretreated
[68]
MPM patients were randomized to receive analog WT1 peptide vaccine galinpepimut-S or placebo. The
results show an increase in mPFS and mOS of 36% and 25%, respectively, in patients treated with the
[69]
vaccine compared to the placebo group .

Based on these promising results, there is currently an ongoing phase I study (NCT04040231) investigating
the safety of galinpepimut-S alone or in combination with nivolumab in pretreated MPM patients.

Additionally, in a phase I clinical trial (NCT01675765), the safety and efficacy of the sequential
administration of CRS-207, an attenuated vaccine of Listeria monocytogenes genetically modified and
engineered to stimulate an immune response against mesothelin (with or without cyclophosphamide) and
chemotherapy, was investigated in MPM patients. The results demonstrate that CRS-207 administration is
safe and the subsequent administration of cisplatin and pemetrexed is well tolerated. In particular, no
patients developed listeriosis. Moreover, a PR was reported in 54% and a SD in 29% of patients enrolled;