Equipping immune cells with synthetic receptors is an important strategy to expand the repertoire of immunotherapies. Two papers in Science describe the development of T cells with synthetic Notch (synNotch) receptors to induce gene circuits that trigger the production of therapeutic payloads to treat central nervous system (CNS) and inflammatory diseases.
Simic et al. engineered a synNotch receptor to sense the brain-specific extracellular matrix protein brevican (BCAN). In this design, the presence of BCAN triggers the expression of a chimeric antigen receptor (CAR) construct in T cells that is targeted toward the ephrin type A receptor 2 (EphA2) and interleukin (IL)-13 receptor a2 (IL13Ra2), which are glioma-associated antigens, in a mouse model of glioblastoma. The CNS-sensing CAR T cells induced tissue-specific killing of primary and secondary brain cancer tumors while sparing off-target tissues outside the brain. Moreover, an anti-BCAN synNotch receptor tailored to induce the expression of IL-10, a potent anti-inflammatory cytokine, alleviated symptoms of neuroinflammation in a mouse model of multiple sclerosis.
