Science Highlights
Published on October 01, 2026
Defining Optimal Notch1 Signaling in CAR T Cells
by Blood
Phillips MK, Birocchi F, Korell F, et al. Rational Engineering of Notch1 Signaling to Boost the Proliferation of CD19-BBζ CAR-T. Blood. 2026; (doi: 10.1182/blood.2026033694).
Notch1 is known for its role in upregulating pro-inflammatory and survival genes in normal T cells, but research suggests the receptor also plays an important part in chimeric antigen receptor (CAR) T cells. Investigators observed that both too much Notch1 signaling, via lentiviral overexpression of Notch1's intracellular domain (N1ICD), and too little Notch1 signaling, as a result of genetic knockout, produce unfavorable outcomes. Either scenario leads to impaired CD19 CAR-T-cell activation and proliferation, resulting in defects in cytotoxicity. Conversely, enhanced proliferation and greater cytotoxicity are possible as a result of mutations in the PEST domain within the N1ICD. The domain regulates Notch1's half-life, and by deleting PEST in the endogenous N1ICD of CAR T cells, scientists were able to increase levels of active Notch1 and prolong its signaling. In in vivo B-ALL xenograft models, exposure to Notch1 PEST-deleted CAR T cells mediated greater tumor reduction and better expansion compared with conventional CAR T cells. The findings indicate that strong effector function depends on a precisely balanced level of Notch1 signaling.
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