# Logic-gated therapeutics (AND, NOT gates)

Source: https://onco.cc/technologies/logic-gated-therapeutics/  
OnCo record `logic-gated-therapeutics` (Technology). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Cells or drugs that fire only when two conditions are true at once, so healthy tissue expressing just one of them is spared.

## Summary

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.

## Fields

- Kind: Technology
- Status: phase-1
- Last checked: 2026-09-08
- Tags: frontier; promising
- Principle: 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.
- Strengths: 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
- Limitations: Complex constructs are harder to manufacture and less potent; Antigen loss defeats AND gates; Very early clinical data

## Sources

- ClinicalTrials.gov: logic-gated CAR T: https://clinicaltrials.gov/search?term=logic%20gated%20CAR%20T

## Connected records

- fronts: [Cell Therapy](https://onco.cc/fronts/cell-therapy/), [Targeted Therapy](https://onco.cc/fronts/targeted-therapy/)
- technologies: [Armoured, logic-gated & next-gen CARs](https://onco.cc/technologies/armored-car/), [Bispecific ADC](https://onco.cc/technologies/bispecific-adc/), [CAR-T cell therapy](https://onco.cc/technologies/car-t/), [In vivo CAR-T](https://onco.cc/technologies/in-vivo-car-t/), [Masked / conditionally active ADC](https://onco.cc/technologies/masked-adc/)
- companies: [Arsenal Biosciences](https://onco.cc/companies/arsenal-bio/), [Sana Biotechnology](https://onco.cc/companies/sana-biotechnology/)
- roadmaps: [Paths to cures: interception, eradication, control](https://onco.cc/roadmaps/cure-paths/), [Radical oncology: what could change the war by 2035](https://onco.cc/roadmaps/frontier-2035/)
- terms: [Antigen escape (antigen loss, lineage switch)](https://onco.cc/terms/antigen-escape/)

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