2025/10/23 by Maria Caterina Rotiroti, Aidan M. Tousley, Hoyin Chu +17 · 1 voice
Medicine · Engineering · Biochemistry, Genetics and Molecular Biology · #CAR-T cell therapy research #Nanowire Synthesis and Applications #Viral Infectious Diseases and Gene Expression in Insects
paper · pdf · doi:10.1038/s43018-025-01056-4
openalex publication_date 2025/10/23 · openalex created_date 2025/10/24 · openalex updated_date 2026/07/31
Chimeric antigen receptor (CAR) T cells can mediate durable complete responses in individuals with certain hematologic malignancies, but antigen downregulation is a common mechanism of resistance. Although the native T cell receptor can respond to very low levels of antigen, engineered CARs cannot, likely due to inefficient recruitment of downstream proximal signaling molecules. We developed a platform that endows CAR T cells with the ability to kill antigen-low cancer cells consisting of a membrane-tethered version of the cytosolic signaling adaptor molecule SLP-76 (MT-SLP-76). MT-SLP-76 can be expressed alongside any CAR to lower its activation threshold, overcoming antigen-low escape in multiple xenograft models. Mechanistically, MT-SLP-76 amplifies CAR signaling through recruitment of ITK and PLCγ1. MT-SLP-76 was designed based on biologic principles to render CAR T cell therapies less susceptible to antigen downregulation and is poised for clinical development to overcome this common mechanism of resistance.