Logic-gated therapeutics (AND, NOT gates)
Cells or drugs that fire only when two conditions are true at once, so healthy tissue expressing just one of them is spared.
SynNotch and similar circuits require antigen A to license killing of antigen B; NOT gates use an inhibitory receptor against an antigen present only on normal tissue. Tmod NOT-gated CAR-T exploiting HLA loss of heterozygosity is in early-phase trials, and AND-gated constructs are in phase 1 for solid tumours. Logic gating is the leading answer to on-target off-tumour toxicity, but circuit complexity reduces potency and manufacturability.
How it works
A synthetic receptor circuit integrates two antigen inputs; killing proceeds only if the required combination is present, and is blocked if a protective antigen is detected.
- Directly addresses the antigen-specificity ceiling in solid tumours
- Turns non-specific antigens into usable targets
- Applies to bispecifics and masked drugs as well as cells
- Complex constructs are harder to manufacture and less potent
- Antigen loss defeats AND gates
- Very early clinical data
Latest papers
topQuery for this technology: (TITLE:"Logic-gated therapeutics" OR ABSTRACT:"Logic-gated therapeutics" OR TITLE:"AND, NOT gates" OR ABSTRACT:"AND, NOT gates") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about Logic-gated therapeutics (AND, NOT gates), not a curated reading list.