Engineering T cells with a membrane-tethered version of SLP-76 overcomes antigen-low resistance to CAR T cell therapy
Year: 2025
Type: article
Abstract: 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.
Source: Nature Cancer
Authors: Maria Caterina Rotiroti, Aidan M. Tousley, Hoyin Chu, Marco Herrera-Barrera, Antigoni Manousopoulou, Won-Ju Kim, Yajie Yin, Thomas Spencer Parish, Aniela Mitchell, Malcolm Holterhus, Lea Wenting Rysavy, Guillermo Nicolas Dalton, Katherine Ann Freitas, Gernot Kaber, Korbinian N. Kropp, Christopher A. Klebanoff, Ansuman T. Satpathy, Leo D. Wang, Caleb A. Lareau, Robbie G. Majzner
Institutions: Dana-Farber Cancer Institute, Stanford Medicine, Stanford University, Memorial Sloan Kettering Cancer Center, Stanford Cancer Institute, Parker Institute for Cancer Immunotherapy, City Of Hope National Medical Center, Boston Children's Hospital, Harvard University, Dana-Farber/Harvard Cancer Center
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Funders: Cancer Research Institute, Amgen, Parker Institute for Cancer Immunotherapy, Mark Foundation For Cancer Research, Cycle for Survival, Cancer Research UK, Deutsche Forschungsgemeinschaft, National Institutes of Health, National Human Genome Research Institute, National Cancer Institute, National Institute of General Medical Sciences, Hyundai Hope On Wheels, Stanford Maternal and Child Health Research Institute
Awards: G1779475623, G2146480081, G3520131408, Hijacking the T cell machinery for logic-gated CAR T cell control, G4102770861, G5109122429, G6393038893, G7267893465, G7699268406, G7772429250, G8008592997, G9000003249, G9000057946, G9000094483, G9000355665, Cancer Center Support Grant, Charting somatic evolution via single-cell multiomics, Molecular mechanisms of T cell responses to a clonal neoantigen resulting from a mutated driver oncogene.
OpenAlex ID: W4415464685