CEA / carcinoembryonic antigen (activator) / HLA-A*02 (blocker)

Class

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

Pathway

Dual-receptor 'NOT-gate' design: CAR activator recognizes CEA on tumor cells while an inhibitory LIR-1-based blocker recognizes HLA-A*02, sparing normal tissue and killing tumor cells with HLA-A*02 loss of heterozygosity

This is a cell-based cancer therapy built from a patient's own T lymphocytes, engineered to carry two receptors that work together as a logic circuit. One receptor, a chimeric antigen receptor (CAR), recognizes carcinoembryonic antigen (CEA), a protein often overexpressed on tumor cells of the gut and other epithelial cancers but also present at low levels on some normal tissues. The second receptor is inhibitory: built from an LIR-1-derived signaling domain, it recognizes a common HLA-A*02 protein, part of the machinery healthy cells use to display markers of self to the immune system. The two receptors are wired so that HLA-A*02 recognition suppresses the killing signal from the CEA receptor, creating a 'NOT-gate.' Many tumors lose one copy of their HLA genes (loss of heterozygosity) during malignant evolution, including the copy encoding HLA-A*02, while retaining CEA expression. In principle, this allows the engineered T cells to kill CEA-positive, HLA-A*02-negative tumor cells while sparing normal tissue that still expresses both CEA and HLA-A*02. The broader rationale is to widen the therapeutic window for CAR T-cell approaches against antigens like CEA that are not truly tumor-exclusive, a persistent limitation in treating solid tumors with cell therapies.