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6.2 months, but a slight improvement in overall survival [19,20] . The combination of nivolumab (anti-PD-1
antibody) plus ipilimumab (anti-CTLA-4 antibody) (NCT03048474, NCT02716272, NCT02899299) resulted
in a PFS of 4.8-6.8 months (OS 15.9-18.1) and further improved MPM response rates (RR) from 25.8 to 29%
[20]
as compared with anti-PD1/ anti-PD-L1 monotherapy . Of note, the MPM patients who seemed to benefit
the most were those with sarcomatoid histology . The promising results of opilimumab/nivolumab
[21]
combination therapy led to the approval of this regime for use as first-line therapy for MPM. As second-line
therapy for MPM, gemcitabine and/or vinorelbine or ICI therapies are used [22-25] . Figure 1 outlines the
currently available therapeutic options for MPM, with the timeline representing the median OS.

In a study by Kim et al., ICIs appeared to benefit patients with advanced MPM after initial platinum-based
[26]
chemotherapy . These findings, however, could not be extrapolated in the PROMISE-meso phase III
randomized clinical trial, which failed to demonstrate the survival benefit of pembrolizumab over
gemcitabine or vinorelbine . Resistance to ICIs is multifactorial, involving the TME, the intrinsic tumoral
[27]
signaling and host genetic factors of which the primary resistance to ICIs in MPM is attributed to the
moderate to low levels of PD-L1 expression with low tumor mutational burden (TMB) . Compared with
[28]
MPM, MPeM has a slightly higher PD-L1 and TMB, and this difference in biology may unravel the ICI
therapy . Despite the clinical, molecular and epidemiological differences, the MPeM treatment strategies
[29]
are largely based on the MPM studies, that is retrospective evidence-based. The overall low response rate for
the second-line treatment drugs warrants further research and patients' referrals for participating in clinical
trials.

CAR-T CELL THERAPY IN MM
Cellular immunotherapy, or adoptive cell therapy, are treatments that utilize the body’s immune cells to
fight cancer. Several cellular immunotherapies exist, such as engineered T cell receptor (TCR) therapy,
tumor-infiltrating lymphocyte (TIL) therapy, and chimeric antigen receptor T (CAR-T) cell therapy, all
demonstrating feasibility of adoptive transfer and treatment successes, especially in hematological
malignancies .
[30]

Cellular immunotherapy research in MM has been mainly focused on CAR-T cell therapy. CAR-T cells are
patient autologous T cells that are genetically re-engineered ex-vivo to express a non-MHC-restricted
receptor (CAR) targeting a specific tumor cell surface antigen. The CAR is composed of an antibody-
derived single-chain variable fragment (scFv) fused to a flexible spacer/hinge region, a transmembrane part,
and an intracellular signaling domain (CD3-ζ or Fc-γ) [31,32] . The CD3ζ intracellular signaling domain of
CARs (or else, 1st generation CARs) was shown to provide limited therapeutic efficacy in initial trials , so
[33]
CAR technology evolved to 2nd and 3rd generation CARs. These newer generation CARs incorporated
additional co-stimulatory molecules, such as CD28, 4-1BB, or OX40, to the CD3ζ primary signaling domain
and exhibited enhanced cell proliferation and greater antitumor potency due to increased signaling
[34]
strength . To date, all the available FDA/EMA/NICE-approved CAR-T cell therapies are either
CD28/CD3ζ or 41BB/CD3ζ second-generation CARs.

CAR-T cell therapies against tumor-associated antigens (TAAs) or stroma-associated proteins have been
developed and trialed in MM. Mesothelin (MSLN) is a cell-surface glycoprotein involved in tumor invasion
and is expressed in 85% to 90% of MMs, with its expression elsewhere limited to the mesothelial surfaces at
low levels [35-37] . Previous research involving MSLN-knockout mice established no histologic or anatomic
abnormalities, suggesting MSLN may be non-essential for normal mouse development or reproduction ,
[38]
making it a great therapeutic target. The majority of current CAR-T cell trials target MSLN in MPM , few
[39]
in MPeM, and a range of solid tumors . Other CAR-T cell targets explored in preclinical studies of MM
[40]