autologous anti-mesothelin T-cell receptor fusion construct/PD-1:CD28 switch receptor-expressing T cells TC-510

A preparation of autologous T lymphocytes that have been genetically engineered to express a single-domain antibody that recognizes human tumor-associated antigen (TAA) mesothelin (MSLN), fused to the N-terminus of the CD3-epsilon T-cell receptor (TCR) subunit which, upon expression is incorporated into the endogenous TCR complex, and a PD-1:CD28 switch receptor composed of the extracellular ligand binding domain of the human inhibitory receptor programmed cell death protein 1 (PD-1; PDCD1) fused to the transmembrane and cytoplasmic co-stimulatory signaling domains of CD28, with potential immunomodulating and antineoplastic activities. Upon reintroduction into the patient, autologous anti-MSLN TCR fusion construct/PD-1:CD28 switch receptor-expressing T cells TC-510 specifically target and bind to MSLN-expressing tumor cells. This leads to T-cell activation and T-cell mediated lysis of MSLN-expressing tumor cells. The switch receptor expressed by the engineered T cells TC-510 targets and binds to the PD-1 ligands, programmed cell death ligand 1 (PD-L1) and 2 (PD-L2), expressed on tumor cells. The nature of the PD-1/CD28 switch receptor fusion protein prevents the normal PD1/PD-L1-mediated T-cell suppression and, instead, promotes signaling through the CD28 domain, which results in the stimulation of T-lymphocytes. This induces enhanced toxicity against tumor cells. Mesothelin, a cell surface glycoprotein involved in cell adhesion, is overexpressed in a variety of cancer cell types.