Targeting Mesothelin via the native T cell receptor

Mesothelin (MSLN) is a GPI-anchored cell surface glycoprotein that is overexpressed in various solid tumors, including mesothelioma, triple-negative breast cancer, colon, ovarian and pancreatic cancer, with restricted normal tissue expression. To explore the immunogenicity and immunotherapeutic potential of MSLN to T cells with native receptor specificity, 29 individuals of diverse HLA backgrounds were interrogated for T cell activity against MSLN. Twenty one (72%) subjects (21/29) mounted a specific T cell response when repetitively challenged with MSLN antigen. Reactive cells were Th1 polarized, polyfunctional, predominantly detected in the CD8+ T cell compartment and cytotoxic toward autologous and MSLN+/HLA-matched tumor cell lines in conventional 2D in vitro assays. Furthermore, these cells produced potent anti-tumor effects in a novel 3D tumor spheroid model system established to evaluate the safety and potency of reactive cells against tumors including pancreatic, cervical, and colorectal cancer and mesothelioma. Taken together, these findings establish the feasibility of targeting MSLN using adoptively transferred T cells with native antigen specificity.