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Page 2 of 15 D'Souza et al. J Cancer Metastasis Treat 2022;8:28 https://dx.doi.org/10.20517/2394-4722.2022.51

INTRODUCTIONS
Malignant mesothelioma (MM) is a rare, highly aggressive malignancy of the mesothelial cells lining the
body’s serosal membranes. The currently well-known cause for the development of MM is exposure to
asbestos, with radiation and BAP-1 germline mutations also being implicated as possible causes . Most
[1]
patients (~75%) are diagnosed with malignant pleural mesothelioma (MPM), which affects the mesothelial
lining of the lung. Around 20% of mesothelioma diagnoses are peritoneal mesothelioma (MPeM)
developing in the peritoneal membrane. Less than 5% of all MM cases primarily develop in the pericardial
membrane, or in the tunica vaginalis in men. Despite treatment advances in recent years, prognosis remains
poor, with a median overall survival (OS) of approximately one year when treated with pemetrexed-
[2,3]
platinum chemotherapy and a 5-year survival of around 10% .

The pemetrexed-platinum combination chemotherapy has remained the mainstay of treatment in MPM
since its introduction 17 years ago and until 2021 . The addition of the anti-angiogenic agent bevacizumab
[4-6]
to pemetrexed/cisplatin chemotherapy improved MPM OS in selected patients from 16.1 to 18.8 months ,
[7,8]
but has not been widely adopted. The multimodality treatment of surgery, radiotherapy, and
pemetrexed/cisplatin chemotherapy has resulted in 5-year survival of only about 5% and is a viable option
for only a small number of MPM patients [9,10] . MM’s advanced stage, localization, and morphology
contribute to its high resistance to therapy. Therefore, there has been a need for more efficient therapies to
be developed and tried in this disease. In recent years, several novel immunotherapies have been developed
and tested in clinical trials, including chimeric antigen receptor (CAR)-T cell immunotherapies [11,12] .

CAR-T cell therapy for MM involves directly targeting tumor surface antigens like the glycoprotein
mesothelin or targeting the tumor stroma through antigens expressed by cancer-associated fibroblasts
(CAFs). The development of efficacious CAR-T cell therapies for advanced solid tumors like MM presents
several significant challenges relating to efficient CAR-T cell trafficking to and infiltration in the tumor,
limited CAR-T cell persistence and exhaustion, and a highly immunosuppressive tumor microenvironment
(TME). Another important challenge is tumor antigen heterogeneity, which refers to the varying and
diverse levels of tumor-associated antigen (TAA) expression across different patients with the same cancer
or even within the same patients at different time points [13,14] .

In this review, we provide an in-depth overview of all aspects of tumor antigen heterogeneity and its
implications in the development of CAR-T cell therapies against MM. Furthermore, we discuss the novel,
innovative CAR-T cell approaches that could significantly contribute to overcoming tumor antigen
heterogeneity, therefore offering CAR-T cells the opportunity to attack and eliminate MM and other solid
tumors more efficiently.

CURRENT TREATMENT LANDSCAPE IN MM
Pemetrexed/cisplatin chemotherapy, the mainstay of MPM treatment, has been combined with targeted
therapies, such as tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib and the mTOR inhibitor
everolimus, but have been so far unsuccessful [15-18] . The treatment for MPeM, according to the National
Comprehensive Cancer Network (NCCN), is first-line platinum-pemetrexed chemotherapy; beyond the
first-line, there has not been any FDA-approved or established treatment regimen for MPeM. MPeM
treatment strategies vary based on the patients’ disease progression state and consensus regarding the
optimal treatment regimen for MPeM is still lacking. More recently, single-agent immune checkpoint
inhibitor (ICI) immunotherapy targeting programmed cell death ligand 1 (PD-L1) (NCT01772004) or
programmed death protein 1 (PD-1) (NCT02399371, NCT02054806, NCT02991482 NCT02716272) have
demonstrated a modest increase in the median progression-free survival (PFS) in MM ranging from 2.5 to