An autologous, genetically engineered Tmod CAR T-cell therapy with a dual-receptor logic gate: an activator CAR targets carcinoembryonic antigen (CEA) and a blocker receptor recognizes HLA-A*02 on normal cells. The cells activate only in CEA-positive tumor cells lacking HLA-A*02 (AND-NOT gating) to spare normal CEA-expressing tissues. Investigated post-lymphodepletion for CEA+ solid tumors with HLA-A*02 loss of heterozygosity.
Autologous T cells engineered with a dual-receptor logic gate: an activating CAR targets CEA to trigger cytotoxicity, while an HLA-A*02–specific inhibitory receptor (LIR-1–based) blocks activation on HLA-A*02–positive normal cells. This AND-NOT gating enables killing only of CEA-positive tumor cells that have lost HLA-A*02. An shRNA against B2M reduces HLA class I expression on the engineered T cells.
YES
DIRECT
Engineered CAR T cells bind CEA via the activator CAR and directly kill CEA+ tumor cells (perforin/granzyme-mediated lysis); activation is blocked on HLA-A*02–positive cells by the inhibitory receptor.
An autologous, genetically engineered Tmod CAR T-cell therapy with a dual-receptor logic gate: an activator CAR targets carcinoembryonic antigen (CEA) and a blocker receptor recognizes HLA-A*02 on normal cells. The cells activate only in CEA-positive tumor cells lacking HLA-A*02 (AND-NOT gating) to spare normal CEA-expressing tissues. Investigated post-lymphodepletion for CEA+ solid tumors with HLA-A*02 loss of heterozygosity.
Autologous T cells engineered with a dual-receptor logic gate: an activating CAR targets CEA to trigger cytotoxicity, while an HLA-A*02–specific inhibitory receptor (LIR-1–based) blocks activation on HLA-A*02–positive normal cells. This AND-NOT gating enables killing only of CEA-positive tumor cells that have lost HLA-A*02. An shRNA against B2M reduces HLA class I expression on the engineered T cells.
NO
INDIRECT
Engagement of HLA-A*02 by the LIR-1-based inhibitory receptor blocks CAR activation, sparing HLA-A*02-positive cells. Cytotoxicity occurs only against CEA-positive, HLA-A*02-negative tumor cells via CAR T-cell killing (perforin/granzymes).
An autologous, genetically engineered Tmod CAR T-cell therapy with a dual-receptor logic gate: an activator CAR targets carcinoembryonic antigen (CEA) and a blocker receptor recognizes HLA-A*02 on normal cells. The cells activate only in CEA-positive tumor cells lacking HLA-A*02 (AND-NOT gating) to spare normal CEA-expressing tissues. Investigated post-lymphodepletion for CEA+ solid tumors with HLA-A*02 loss of heterozygosity.
Autologous T cells engineered with a dual-receptor logic gate: an activating CAR targets CEA to trigger cytotoxicity, while an HLA-A*02–specific inhibitory receptor (LIR-1–based) blocks activation on HLA-A*02–positive normal cells. This AND-NOT gating enables killing only of CEA-positive tumor cells that have lost HLA-A*02. An shRNA against B2M reduces HLA class I expression on the engineered T cells.
NO
INDIRECT
A2B530 kills CEA-positive, HLA-A*02–negative tumor cells via CAR T cell cytolysis (perforin/granzyme). Beta-2-microglobulin is only knocked down within the engineered T cells and is not a target for killing on tumor cells.
Antibody–drug conjugate targeting CD79b on B cells; after internalization releases MMAE (microtubule inhibitor) causing cell-cycle arrest and apoptosis.
CD79b-targeted monoclonal antibody delivers the microtubule inhibitor MMAE via a cleavable linker; after binding and internalization in B cells, MMAE is released to inhibit tubulin polymerization, causing G2/M cell-cycle arrest and apoptosis of malignant B cells.
YES
DIRECT
ADC binds CD79b on B cells, is internalized, linker is cleaved to release MMAE, which inhibits tubulin polymerization causing G2/M arrest and apoptosis.
Antibody–drug conjugate targeting CD79b on B cells; after internalization releases MMAE (microtubule inhibitor) causing cell-cycle arrest and apoptosis.
CD79b-targeted monoclonal antibody delivers the microtubule inhibitor MMAE via a cleavable linker; after binding and internalization in B cells, MMAE is released to inhibit tubulin polymerization, causing G2/M cell-cycle arrest and apoptosis of malignant B cells.
NO
INDIRECT
Polatuzumab vedotin binds CD79b on B cells, is internalized, and releases MMAE, which binds the Vinca site on beta-tubulin to disrupt microtubules, causing G2/M arrest and apoptosis. Tubulin expression itself does not determine targeting; CD79b does.