EGFR (activator) / HLA-A*02 (blocker)

Class

Allogeneic logic-gated (Tmod) CAR T-cell therapy

Pathway

Dual-receptor 'NOT-gate' design: CAR activator recognizes EGFR on tumor cells while an inhibitory LIR-1-based blocker recognizes HLA-A*02, sparing normal EGFR+/HLA-A*02+ tissue and killing tumor cells that have lost HLA-A*02 (loss of heterozygosity)

This is a logic-gated chimeric antigen receptor (CAR) T-cell therapy designed to distinguish tumor cells from healthy tissue using two receptors on the same engineered T cell. The 'activator' receptor recognizes EGFR, a cell-surface protein expressed on many solid tumors but also on numerous normal tissues, which makes EGFR alone a poor target because it would cause damage to healthy cells. The second receptor, the 'blocker,' recognizes HLA-A*02, a component of the machinery that displays protein fragments on the cell surface for immune surveillance. Many tumors lose one copy of HLA-A*02 (a phenomenon called loss of heterozygosity) as a way to evade the immune system, while retaining EGFR expression. The T cell is engineered so that the blocker signal overrides the activator, sparing any cell that still expresses HLA-A*02. Only cells with EGFR present and HLA-A*02 lost are killed. This 'NOT-gate' logic aims to give tumor selectivity that a conventional single-target EGFR CAR-T could not achieve, broadening the potential use of EGFR as a target across solid tumors where on-target, off-tumor toxicity would otherwise be limiting.