T-cell receptor recognizing mesothelin-derived peptide–MHC complexes (MSLN-TCR)

The T-cell receptor (TCR) recognizing mesothelin-derived peptide–MHC complexes is a recombinant or naturally derived receptor utilized in TCR-engineered T-cell (TCR-T) therapies for solid tumors [4, 9]. Mesothelin is a cell-surface glycoprotein that is significantly overexpressed in several aggressive cancers, including mesothelioma, pancreatic ductal adenocarcinoma, and ovarian cancer [3, 12]. These specialized TCRs are designed to bind with high affinity to specific mesothelin-derived peptides, such as SLLFLLFSL or VLPLTVAEV, when presented by Major Histocompatibility Complex (MHC) molecules like HLA-A*02:01 [9, 13]. Binding of the TCR to the peptide-MHC complex triggers the activation of the T-cell's signaling machinery, primarily through the CD3 complex, leading to the release of cytotoxic cytokines and granzymes [10, 15]. This mechanism allows the engineered T-cells to selectively identify and eliminate malignant cells that present these intracellularly processed antigens on their surface [1, 4]. Clinical candidates such as FH-TCR-TMSLN are currently being evaluated in phase I trials to determine their safety and efficacy in patients with metastatic disease [9, 27]. A significant therapeutic challenge is "on-target, off-tumor" toxicity, as mesothelin is also expressed at lower levels on normal mesothelial cells in the pleura and peritoneum [6, 11]. Additionally, the immunosuppressive microenvironment of solid tumors can hinder the persistence and activity of TCR-T cells, necessitating strategies like lymphodepletion or combination with checkpoint inhibitors [8, 15]. Monitoring for cytokine release syndrome (CRS) and neurotoxicity is essential during treatment due to the potent immune activation induced by these receptors [7, 9]. Overall, this TCR-based approach represents a promising frontier in precision oncology, aiming to extend the success of cellular immunotherapies to solid malignancies [3, 30].

Other names

Mesothelin-specific T-cell receptorAnti-mesothelin TCRMSLN-TCRTCR-TMSLN

Adoptive T-cell therapy (TCR-T) involving the recognition of mesothelin-derived peptides presented by MHC class I molecules (e.g., HLA-A*02:01), leading to T-cell activation and tumor cell lysis.