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Page 2 of 12 Bongiovanni et al. J Cancer Metastasis Treat 2022;8:44 https://dx.doi.org/10.20517/2394-4722.2022.78

[1]
indicates that it has become an epidemic . According to histology, MPM is distinguished into three groups:
[2,3]
epithelioid, sarcomatoid, and biphasic type . Due to its rapid growth, MPM is generally diagnosed at an
advanced stage; consequently, only few patients are suitable for the radical surgical approach (pleuro-
pneumonectomy or radical pleural decortication), usually associated with neoadjuvant chemotherapy and
adjuvant radiation therapy. Front-line systemic treatment with platinum compounds combined with
pemetrexed has been the treatment choice for the majority of MPM patients for almost two decades .
[4,5]
However, the antitumor efficacy of this regimen is unsatisfactory, with the median overall survival (mOS) of
approximately 12 months. Over the last decade, research showed that the angiogenesis process seems to
have a key role in MPM progression, which led to the investigation of several antiangiogenetic agents in
prospective clinical trials. However, with the exception of the MAPS trial, in which bevacizumab combined
with a platinum-based regimen showed a significant improvement in survival compared with chemotherapy
alone despite the cardiovascular side effects reported , the trials, including the randomized, phase III
[6]
LUME-Meso-study with nintedanib combined with chemotherapy, failed to demonstrate a survival
benefit . Furthermore, the outcome results of second-line regimens approved for relapsed MPM patients
[7]
were not satisfactory; gemcitabine, vinorelbine, or pemetrexed rechallenge was often utilized in this setting
of disease for fit MPM patients, but without a significant improvement in mOS .
[8]

In the last years, targeting checkpoint inhibitors has dramatically redesigned the therapeutic landscape of
different tumor types, and promising results in unresectable MPM subjects, particularly combination
regimens, have been recently reported. Consistently, ipilimumab, an anti-cytotoxic T lymphocyte antigen
(CTLA)-4 monoclonal antibody (mAb), in combination with nivolumab, an anti-programmed cell death
protein (PD)-1 mAb, demonstrated greater efficacy than platinum-based standard regimen in first-line
MPM patients, and it has very recently become the new standard of care in several countries .
[9]

This review critically discusses the recent strategies with immunotherapeutic approaches and those
currently under investigation.

METHODS
A comprehensive search strategy of the currently available literature on PubMed, PMC, and NLM databases
was performed to identify published studies involving immune checkpoint inhibitors (ICIs) and other
immune-therapeutic approaches for the treatment of MPM patients. Furthermore, congress material from
the most important oncology conferences held by international associations, including the American
Society for Clinical Oncology (ASCO), the International Association for the Study of Lung Cancer (IASLC),
the European Society for Medical Oncology (ESMO), and the International Mesothelioma Interest Group,
were also evaluated.

Immuno-oncology: immune checkpoint inhibitors
Up to 2020, no treatments succeeded the platinum-pemetrexed combination regimen in association with or
without bevacizumab as a first-line option for unresectable MPM [5,6,8] .

Indeed, new effective therapeutic agents have been frustratingly slow to develop. This dramatic scenario has
recently changed with the phase III CheckMate 743 trial , which showed a statistically significant
[10]
improvement in survival with nivolumab plus ipilimumab compared to chemotherapy, thereby licensing
this new regimen as the first choice for advanced MPM subjects in most countries. This approval followed a
long course of clinical studies with CTLA-4/PD-1/PD-ligand(L)-1 blocking agents used alone or in
combination showing signs of antitumor activity [Figure 1], mostly conducted in pretreated MPM patients,
a setting in which therapeutic options are very limited [11,12] .