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Bongiovanni et al. J Cancer Metastasis Treat 2022;8:44 https://dx.doi.org/10.20517/2394-4722.2022.78 Page 7 of 12

[33]
October 2020, followed by the European Medicines Agency (EMA) approval in June 2021 .

Is chemotherapy combined with ICI the next step?
Great efforts are currently addressing novel combination regimens to enhance the efficacy of
immunotherapy and overcome primary resistance to treatment, largely observed in most cancer
patients [34-38] . Along this line, chemotherapy could be an interesting partner for a combination regimen with
immunotherapy, in view of its immunomodulatory properties. Currently, different trials investigating the
efficacy of platinum-pemetrexed combined with ICIs are ongoing.

In the phase II PrE505 study, first-line MPM patients received treatment with platinum-pemetrexed in
combination with the anti-PD-L1 durvalumab . Updated results show a remarkable mOS of 20.4 months
[39]
[39]
(95%CI: 13.0-28.5) with a one-year OS rate of 70.4% . Furthermore, the study provided an interesting ORR
of 56.4% (95%CI: 42.3-69.7%). In the phase II Dream study, patients were treated with a platinum-based
regimen plus pemetrexed in combination with durvalumab used at the fixed dose of 1125 mg for six cycles,
followed by durvalumab maintenance for up to one year. The study showed a six-month PFS rate of 57% .
[40]
Based on these promising results, the phase III Dream3r study is ongoing .
[41]
Two additional studies are currently ongoing: In the randomized, front-line phase III IND227 trial
(NCT02784171), MPM patients receive platinum-based chemotherapy plus the anti-PD-1 pembrolizumab
or chemotherapy alone. The study has completed the accrual, and the results are awaited. The actively
recruiting phase III BEAT-Meso study s exploring the efficacy of chemotherapy plus bevacizumab and
atezolizumab vs. only chemotherapy in first-line MPM patients (NCT03762018).

Results from the phase III studies are urgently awaited, and if positive, they could enrich the therapeutic
approaches in this setting of disease.

Immune-oncology: not only ICI
Mesothelin (MSLN) is a membrane protein predominantly expressed in both normal and malignant
mesothelial cells, above all in the epithelioid histological subtype. For these reasons, it appears to be an
optimal candidate for targeted therapies . The preliminary antitumor effect observed in preclinical studies
[42]
led to the design of a phase I trial using T cells expressing a second-generation murine anti-mesothelin
chimeric antigen receptor (CAR) [43,44] . No clinical response or “on target” toxicities were recorded, but
interestingly an immunogenicity reaction to the murine SS1 scFv used in the CAR construct was noted .
[45]
Given these premises, a second phase I trial (NCT02159716) was conducted. Fifteen patients affected by
different tumor types including mesothelioma received a lentiviral transduction vector expressing a second-
generation murine-based anti-mesothelin CAR . Cyclophosphamide was used as pretreatment to enhance
[46]
CAR-T expansion. No complete responses (CR) or PR were reported, but a SD was found in 11/15
[46]
patients . At the University of Pennsylvania, another trial is ongoing using both intravenous and
intrapleural administration of a fully human anti-mesothelin CAR in combination with cyclophosphamide
(NCT03054298). In a recently published phase I/II trial, mesothelin-targeting CAR-T cells were safely
administered with an intrapleural injection to 31 patients, with no procedure-related adverse events greater
than grade 1 .
[47]
In another phase I/II trial, 25 pretreated MPM patients received an intrapleural administration of a MSLN
targeting CAR T cell therapy either alone or followed by pembrolizumab . Pembrolizumab was
[48]
administered after CAR-T cell therapy in 18 patients. Promising results were observed, with an mOS of 23.9
months and a one-year OS of 83% . Together with MSLN, fibroblast activation protein (FAP) and Wilms
[48]