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Page 4 of 15 D'Souza et al. J Cancer Metastasis Treat 2022;8:28 https://dx.doi.org/10.20517/2394-4722.2022.51

Figure 1. The current therapeutic landscape of malignant pleural mesothelioma (MPM). A list of the first and second/third-line
therapies in relation to their median overall survival (mOS). *FDA/EMA/NICE approval (for Nivolumab-Ipilimumab, FDA approval was
granted in 2020, and EMA/NICE approval in 2021). Vin: Vinorelbine; Gem: gemcitabine.

[41]
[42]
include the ErbB family of receptors , the oncofetal glycoprotein 5T4 , chondroitin sulfate proteoglycan 4
(CSPG4) , MET and alkaline phosphatase placental-like 2 (ALPE2) .
[43]
[44]
[45]
In addition to directly targeting the tumor, CARs that target the tumor-associated stroma are gaining
importance in CAR-T cell therapy, and are of great interest in fibrotic tumors like MM. Fibroblast
activation protein (FAP) is a stromal antigen present on cancer-associated fibroblasts (CAFs), endothelial
cells, and on the surface of some mesothelioma cells [46,47] . FAP-expressing CAFs are present in all three
major MPM subtypes, so a number of preclinical studies and a clinical trial investigated FAP CAR-T cells’
therapeutic potential in MM [48,49] . Table 1 summarises the ongoing CAR-T cell therapy trials in MM.

There are several challenges that CAR-T cell therapy faces in solid tumors, like mesothelioma. These
include (i) poor CAR-T cell trafficking to the tumor site and reduced infiltration in the tumor; (ii) the
immunosuppressive effects of the tumor microenvironment (TME); (iii) upregulation of inhibitory
receptors; (iv) CAR-T cell reduced proliferative ability, limited persistence and exhaustion. In addition,
tumor antigen heterogeneity plays a significant role in efficacious CAR-T cell therapy.

TUMOR ANTIGEN HETEROGENEITY
The expression of tumor cell surface antigens, like CD19, in hematological malignancies is relatively
uniform and stable. In contrast, solid tumor cell surface antigens are rarely universally expressed; instead,
they present heterogeneity in their distribution and concentration, and are termed tumor-associated
antigens (TAAs). TAA heterogeneity is a significant yet understudied issue in CAR-T- cell therapy for solid
tumors .
[13]

Tumor heterogeneity in MM has been observed at many levels that overall contribute to the tumor’s
aggressiveness and pose an obstacle to therapy. Intertumor heterogeneity is common in MM, with
molecular analyses revealing an epithelioid-sarcomatoid type between patients’ tumors rather than distinct