Engineering T cells with a membrane-tethered version of SLP-76 overcomes antigen-low resistance to CAR T cell therapy
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.
Authors
- Won‐Ju Kim (ORCID: https://orcid.org/0000-0002-1800-0485)
- Lea Wenting Rysavy (ORCID: https://orcid.org/0009-0006-2290-6630)
- Thomas Parish
- Hoyin Chu (ORCID: https://orcid.org/0000-0001-8630-3667)
- Korbinian N. Kropp (ORCID: https://orcid.org/0000-0001-8104-7166)
- Robbie G. Majzner (ORCID: https://orcid.org/0000-0001-6969-8011)
- Malcolm Holterhus (ORCID: https://orcid.org/0000-0002-0317-1097)
- Katherine A. Freitas (ORCID: https://orcid.org/0000-0001-9480-7320)
- Yajie Yin (ORCID: https://orcid.org/0000-0002-2220-005X)
- Antigoni Manousopoulou (ORCID: https://orcid.org/0000-0001-5028-1865)
- Caleb A. Lareau (ORCID: https://orcid.org/0000-0003-4179-4807)
- Marco Herrera‐Barrera (ORCID: https://orcid.org/0000-0001-7593-907X)
- Ansuman T. Satpathy (ORCID: https://orcid.org/0000-0002-5167-537X)
- Leo D. Wang (ORCID: https://orcid.org/0000-0002-2945-9005)
- Maria Caterina Rotiroti (ORCID: https://orcid.org/0000-0002-3214-1540)
- Christopher A. Klebanoff (ORCID: https://orcid.org/0000-0001-9645-3896)
- Guillermo Nicolás Dalton (ORCID: https://orcid.org/0000-0002-3892-807X)
- Aidan M. Tousley (ORCID: https://orcid.org/0000-0002-3286-0238)
- Gernot Kaber (ORCID: https://orcid.org/0000-0002-6184-5192)
- Alison Mitchell
Institutions
- Boston Children's Hospital (US)
- City Of Hope National Medical Center (US)
- Memorial Sloan Kettering Cancer Center (US)
- Parker Institute for Cancer Immunotherapy (US)
- Dana-Farber Cancer Institute (US)
- Dana-Farber/Harvard Cancer Center (US)
- Broadata Communications (United States) (US)
- Stanford University (US)
Publication Details
- Journal
- Nature Cancer
- Published
- 2025-10-23
- DOI
- https://doi.org/10.1038/s43018-025-01056-4
- Citations
- 2
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 2.09
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 Cancer Institute
- Hyundai Hope On Wheels
- Stanford Maternal and Child Health Research Institute