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CAR-T cells may show second receptor before first recognizes target On August 31 the authors posted a preprint describing a two‑step CAR‑T strategy in which the synthetic SynNotch receptor detects high HER2 density and then activates a CAR that kills the target. In some T cells the CAR appeared on the surface before the SynNotch signal arrived. In three different constructs the basal CAR surface level was measured at 6%, 2%, and 0.2% of resting T cells. The construct with the highest background (6%) showed the poorest ability to discriminate between high‑ and low‑HER2 cells. In a two‑tumor mouse model the high‑background construct reduced both high‑ and low‑HER2 tumors. After binding HER2, CAR triggers T‑cell proliferation, so even a small initial CAR‑positive fraction can shape the whole population. The authors’ mathematical model incorporated the fraction of such cells, HER2 density, and the T‑cell‑to‑target ratio; experiments indicated that optimal discrimination required different T‑cell doses for each construct. To lower basal CAR expression they attached the mScarlet tag to the CAR C‑terminus, which cut the background by about 60% while preserving signal‑induced CAR. Degron tags reduced background further in culture, but T cells bearing degrons lost cytotoxic activity more quickly after CAR activation. In mouse models, mScarlet improved discrimination, suppressing high‑antigen tumors while low‑antigen tumors continued to grow. For the two‑step CAR‑T design, both the timing of CAR expression and its residual level after proper signaling are crucial. Rohelo Hernandez‑Lopez et al., 2021 🔗 Read original →