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Fig. 2 | Biomarker Research

Fig. 2

From: Anti-Mesothelin CAR T cell therapy for malignant mesothelioma

Fig. 2

Barriers to MSLN CAR T cell activity in MM (in red) and strategies to overcome them (in green). a Low tumor infiltration caused by the physical barrier of the stroma in MM could be overcome by intrapleural or intraperitoneal delivery of anti-MSLN CAR T cells or by expressing the CCR2b chemokine receptor on anti-MSLN CAR T cells, which attracts them to the tumor. Combination with a vaccinia virus expressing CXCL11 may also increase anti-MSLN CAR T cell trafficking to the tumor. b Soluble immunosuppression mediators prostanglandin E (PGE2), adenosine and TGF-β contribute to the reduction of anti-tumor activity of anti-MSLN CAR T cells. Strategies that successfully rescued anti-MSLN CAR T cell anti-tumor activity include the knock out (KO) of receptors for TGFβ (TGFBR2) and adenosine (A2AR), the deletion of diacylglycerol kinase (dgk), and the insertion of a ‘regulatory subunit I anchoring disruptor’ (RIAD) in anti-MSLN CAR T cells. The combination of anti-MSLN CAR T cells with TGF-β-targeting oncolytic viruses and TNFα-IL2-producing oncolytic viruses has also helped enhance their efficacy. c Exhaustion due to PD-1/PD-L1 signaling can be counteracted via knock out of PD-1 via CRISPR/Cas9 or by inserting a PD-1 DNR or a PD-1/CD28 switch receptor. Engineering of CAR T cells to secrete anti-PD-1 antibodies has also been studied. d Anti-MSLN CAR T cells with improved CAR design have been shown to have increased persistence and efficacy in mouse models. e CAR T safety can be improved by limiting ‘on target/off tumor’ toxicities through the introduction of a suicide switch in anti-MSLN CAR T cells or the use of mRNA anti-MSLN CAR with transient expression

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