{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["33(4)"],"submitter":["Leleux J"],"pubmed_abstract":["Chimeric antigen receptor (CAR) T cells are effective cancer therapies, particularly in indications with high, stable, and tumor-specific antigen expression. Other settings may require improved targeting sensitivity, controllable targeting selectivity, and/or additional potency enhancements to achieve robust efficacy. Here, we describe a novel receptor architecture called RESET (rapamycin-enabled, switchable endogenous T cell receptor) that combines (1) cell surface antigen targeting, (2) small-molecule regulation, and (3) the signaling proficiency and inherent sensitivity of native T cell receptors. RESET-T cells outperformed both constitutive and drug-regulated CAR-T cells and show hallmarks of TCR activation that suggest improved fidelity to native T cell responses. Pharmacological control then increases safety through toggling T cell activation between active and resting states and may mitigate T cell exhaustion caused by continuous antigen exposure. This convergence of drug-regulated targeting and natural immune receptor signal transduction may better replicate the kinetics and physiology of a classical T cell response and potentiate more successful and safer immunotherapies."],"journal":["Molecular therapy : the journal of the American Society of Gene Therapy"],"pagination":["1608-1620"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11997482"],"repository":["biostudies-literature"],"pubmed_title":["RESET: A TCR-coupled antigen receptor with superior targeting sensitivity and reversible drug-regulated anti-tumor activity."],"pmcid":["PMC11997482"],"pubmed_authors":["Jarjour J","Gregory PD","Sonzogni O","Jin N","Walker RL","Rosenberg J","Garrison SM","Venkitaraman A","Leleux J"],"additional_accession":[]},"is_claimable":false,"name":"RESET: A TCR-coupled antigen receptor with superior targeting sensitivity and reversible drug-regulated anti-tumor activity.","description":"Chimeric antigen receptor (CAR) T cells are effective cancer therapies, particularly in indications with high, stable, and tumor-specific antigen expression. Other settings may require improved targeting sensitivity, controllable targeting selectivity, and/or additional potency enhancements to achieve robust efficacy. Here, we describe a novel receptor architecture called RESET (rapamycin-enabled, switchable endogenous T cell receptor) that combines (1) cell surface antigen targeting, (2) small-molecule regulation, and (3) the signaling proficiency and inherent sensitivity of native T cell receptors. RESET-T cells outperformed both constitutive and drug-regulated CAR-T cells and show hallmarks of TCR activation that suggest improved fidelity to native T cell responses. Pharmacological control then increases safety through toggling T cell activation between active and resting states and may mitigate T cell exhaustion caused by continuous antigen exposure. This convergence of drug-regulated targeting and natural immune receptor signal transduction may better replicate the kinetics and physiology of a classical T cell response and potentiate more successful and safer immunotherapies.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Apr","modification":"2026-06-02T20:14:18.76Z","creation":"2026-04-20T03:10:11.394Z"},"accession":"S-EPMC11997482","cross_references":{"pubmed":["39980194"],"doi":["10.1016/j.ymthe.2025.02.026"]}}