Maria Caterina Rotiroti, Aidan M. Tousley, Hoyin Chu, Marco Herrera‐Barrera, Antigoni Manousopoulou, Won‐Ju Kim, Yajie Yin, Thomas Parish, Aniela Mitchell, Malcolm Holterhus, Lea Wenting Rysavy, Guillermo Nicolás Dalton, Katherine A. Freitas, Gernot Kaber, Korbinian N. Kropp, Christopher A. Klebanoff, Ansuman T. Satpathy, Leo D. Wang, Caleb A. Lareau, Robbie G. Majzner
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.