Mesothelin/MSLN (activator) / HLA-A*02 (blocker)

Class

Autologous logic-gated (Tmod) CAR T-cell therapy with cytokine (IL-12) enhancement

Pathway

Dual-receptor 'NOT-gate' design: CAR activator recognizes mesothelin on tumor cells, blocker recognizes HLA-A*02 to spare normal tissue; inducible membrane-tethered IL-12 boosts T-cell effector function

Notes

original target text: Mesothelin/MSLN (activator) / HLA-A*02 (blocker), plus membrane-tethered IL-12 booster | original target text: Mesothelin/MSLN (activator) / HLA-A*02 (blocker), plus

Mesothelin is a protein anchored to the surface of cells that lines body cavities and is also displayed at high levels on many solid tumors, including mesothelioma and certain ovarian and pancreatic cancers. Because normal mesothelial tissue also carries some mesothelin, a chimeric antigen receptor (CAR) T-cell therapy that simply targets mesothelin risks attacking healthy tissue as well as tumor. This mechanism addresses that problem with a dual-receptor, 'NOT-gate' design: one receptor (the activator) recognizes mesothelin and drives T-cell killing, while a second receptor (the blocker) recognizes a common human leukocyte antigen (HLA) variant, HLA-A*02. Many tumors lose one copy of their HLA genes during malignant transformation, so a tumor cell may display mesothelin without the matching HLA-A*02, allowing the activator signal through unopposed. Normal tissue, which retains HLA-A*02, engages the blocker and is spared. A membrane-anchored form of the cytokine interleukin-12 is included to strengthen T-cell effector activity within the tumor microenvironment, where solid tumors typically suppress immune responses. This general design strategy is broadly relevant to any CAR-based therapy targeting antigens shared between tumor and normal tissue, aiming to widen the safety margin without sacrificing anti-tumor activity.