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

that then kill tumor cells in different ways, potentially by inducing a broader immune response in the
patient. Novel CAR designs, such as multi-antigen targeted CARs (dual/triple TAA-targeted CARs), tandem
CARs (TanCARs), armored CARS, switchable CARs, and synNotch CARs in combination with inhibitory
CARs are currently being investigated and are discussed in this review [79-85] .

Novel CAR strategies
Tumor cells expressing low levels of a targeted TAA may survive following CAR-T cell therapy, as opposed
to those with high levels of the TAA that are preferentially eliminated [86,87] . Therefore, solid tumors that are
heterogeneous in nature may not benefit from single-antigen targeting CAR-T cell therapy. Previous studies
have confirmed the efficiency of CAR-T cell therapy that simultaneously targets two TAAs, for example,
[89]
[88]
MSLN and EpCAM , or MSLN and MUC16 . To further widen the spectrum of antitumor function,
CARs can be modified to produce inhibitory peptides, cytokines, chemokine receptors, and
immunomodulatory agents to target the TME; these are known as armored CARs [90,91] . The inhibitory CAR
(iCAR) fuses an antigen recognition domain, mostly an antigen expressed on normal tissue, with an
inhibitory intracellular domain, PD-1 or CTLA-4. Co-transduction with a regular CAR leads to the
activation of the iCAR, which can inhibit the activity of the co-expressed CAR, thereby limiting the
undesired CAR activation . Other improved CAR designs include tandem CARs (TanCAR) and
[92]
[79]
[93]
switchable CARs , which specifically expand the range of TAAs that can be simultaneously targeted.
Bispecific CAR-T cells are designed by engineering a single CAR molecule with two or more distinct
binding domains. Multi-target CAR-T cell therapies are produced by mixing different CAR-T cell products
targeting single antigens before infusion or transducing T cells with multiple CAR constructs CAR-T cells
[94]
expressing bispecific T cell engagers (BiTEs) recruit bystander T cells against a second TAA . The
synNotch CAR-T cells offer benefits beyond enhanced tumor specificity by preventing premature T cell
differentiation and exhaustion, further enabling T cells to maintain a long-lived memory [45,85] . Figure 2
shows the schematic representation of all the novel CARs designs discussed in this review.

Combination of CAR-T cells and checkpoint inhibitors
Limited engraftment and persistence of CAR-T cells are generally observed in solid tumors post infusion.
One of the ways to ease this is by regional administration of CAR-T cells, where possible. In a recent MPM
study, local, intrapleural delivery of MSNL-targeted CAR-T cells, followed by administration of
Pembrolizumab, demonstrated promising survival outcomes, with a median OS of 23.9 months, despite
[81]
including patients with mesothelin-positive MPM as low as 10% . This study highlights the potential of
CAR-T cell therapy in solid tumors such as MPM. CAR-T cells’ precise antitumor immune response can be
further amplified by the addition of ICI agents that counteract the immune suppressive TME that
undermines optimal CAR-T cell efficacy. A review paper by Chintal et al. on MPM and other solid tumors
explores the advantage of combination immunotherapy strategies to enhance endogenous and adoptively
transferred immunity . In a recent paper, Raghav et al. investigated two drugs, PD-L1 (atezolizumab) and
[95]
vascular endothelial growth factor (VEGF) (bevacizumab) blockade, in 20 patients with advanced MPeM
either after progression or intolerance to prior pemetrexed based chemotherapy . Efficacy of AtezoBevo in
[29]
relation to response rates and survival in advanced MPeM previously treated with chemotherapy surpassed
outcomes with a median progression-free survival (PFS) of 17.6 months, and one-year OS of 85%. Further,
MPeM biomarker analysis revealed epithelial-mesenchymal transition phenotype which was associated with
therapeutic resistance to both AtezoBevo combination and prior to platinum-pemetrexed chemotherapy,
even among patients with epithelioid subtype . Combination immunotherapies comprising CAR-T cells
[29]
and ICI agents are currently under clinical trial investigation.